The Journal of Experimental Medicine via MedWorm.com MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'The Journal of Experimental Medicine' source. Thu, 09 Feb 2012 09:15:17 +0100 Gfi1b negatively regulates Rag expression directly and via the repression of FoxO1 http://www.medworm.com/index.php?rid=5602509&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F187%3Frss%3D1 Precise regulation of Rag (recombination-activating gene) expression is crucial to prevent genomic instability caused by the generation of Rag-mediated DNA breaks. Although mechanisms of Rag activation have been well characterized, the mechanism by which Rag expression is down-regulated in early B cell development has not been fully elucidated. Using a complementary DNA library screen, we identified the transcriptional repressor Gfi1b as negative regulator of the Rag locus. Expression of Gfi1b causes repression of Rag1 and Rag2 in cell lines and primary mouse cells. Conversely, Gfi1b-deficient cell lines exhibit increased Rag expression, double-strand breaks and recombination, and cell cycle defects. In primary cells, transcription of Gfi1b inversely correlates with Rag transcription, and ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602509 Mon, 16 Jan 2012 05:00:00 +0100 5602509 The E3 ubiquitin ligase Mule acts through the ATM-p53 axis to maintain B lymphocyte homeostasis http://www.medworm.com/index.php?rid=5602508&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F173%3Frss%3D1 Cellular homeostasis is controlled by pathways that balance cell death with survival. Mcl-1 ubiquitin ligase E3 (Mule) is an E3 ubiquitin ligase that targets the proapoptotic molecule p53 for polyubiquitination and degradation. To elucidate the role of Mule in B lymphocyte homeostasis, B cell–specific Mule knockout (BMKO) mice were generated using the Cre–LoxP recombination system. Analysis of BMKO mice showed that Mule was essential for B cell development, proliferation, homeostasis, and humoral immune responses. p53 transactivation was increased by two- to fourfold in Mule-deficient B cells at steady state. Genetic ablation of p53 in BMKO mice restored B cell development, proliferation, and homeostasis. p53 protein was increased in resting Mule-deficient mouse embryonic fibro... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602508 Mon, 16 Jan 2012 05:00:00 +0100 5602508 High-mobility group nucleosome-binding protein 1 acts as an alarmin and is critical for lipopolysaccharide-induced immune responses http://www.medworm.com/index.php?rid=5602507&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F157%3Frss%3D1 In this study, we report the identification of HMGN1 (high-mobility group nucleosome-binding protein 1) as a novel alarmin and demonstrate that it contributes to the induction of antigen-specific immune responses. HMGN1 induced DC maturation via TLR4 (Toll-like receptor 4), recruitment of APCs at sites of injection, and activation of NF-B and multiple mitogen-activated protein kinases in DCs. HMGN1 promoted antigen-specific immune response upon co-administration with antigens, and Hmgn1–/– mice developed greatly reduced antigen-specific antibody and T cell responses when immunized with antigens in the presence of lipopolysaccharide (LPS). The impaired ability of Hmgn1–/– mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602507 Mon, 16 Jan 2012 05:00:00 +0100 5602507 Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon http://www.medworm.com/index.php?rid=5602506&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F139%3Frss%3D1 Dendritic cells (DCs) and macrophages (MPs) are important for immunological homeostasis in the colon. We found that F4/80hiCX3CR1hi (CD11b+CD103–) cells account for 80% of mouse colonic lamina propria MHC-IIhi cells. Both CD11c+ and CD11c– cells within this population were identified as MPs based on multiple criteria, including an MP transcriptome revealed by microarray analysis. These MPs constitutively released high levels of IL-10 at least partially in response to the microbiota via an MyD88-independent mechanism. In contrast, cells expressing low to intermediate levels of F4/80 and CX3CR1 were identified as DCs based on phenotypic and functional analysis and comprise three separate CD11chi cell populations: CD103+CX3CR1–CD11b– DCs, CD103+CX3CR1–CD11b+ DCs,... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602506 Mon, 16 Jan 2012 05:00:00 +0100 5602506 Rapid monocyte kinetics in acute myocardial infarction are sustained by extramedullary monocytopoiesis http://www.medworm.com/index.php?rid=5602505&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F123%3Frss%3D1 Monocytes (Mo) and macrophages (M) are emerging therapeutic targets in malignant, cardiovascular, and autoimmune disorders. Targeting of Mo/M and their effector functions without compromising innate immunity’s critical defense mechanisms first requires addressing gaps in knowledge about the life cycle of these cells. Here we studied the source, tissue kinetics, and clearance of Mo/M in murine myocardial infarction, a model of acute inflammation after ischemic injury. We found that a) Mo tissue residence time was surprisingly short (20 h); b) Mo recruitment rates were consistently high even days after initiation of inflammation; c) the sustained need of newly made Mo was fostered by extramedullary monocytopoiesis in the spleen; d) splenic monocytopoiesis was regulated by IL-1β; a... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602505 Mon, 16 Jan 2012 05:00:00 +0100 5602505 Targeting self- and foreign antigens to dendritic cells via DC-ASGPR generates IL-10-producing suppressive CD4+ T cells http://www.medworm.com/index.php?rid=5602504&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F109%3Frss%3D1 This study provides a new strategy for the establishment of antigen-specific IL-10–producing suppressive T cells in vivo by targeting whole protein antigens to DCs via DC-ASGPR. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602504 Mon, 16 Jan 2012 05:00:00 +0100 5602504 Reduced CD36-dependent tissue sequestration of Plasmodium-infected erythrocytes is detrimental to malaria parasite growth in vivo http://www.medworm.com/index.php?rid=5602503&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F93%3Frss%3D1 Adherence of parasite-infected red blood cells (irbc) to the vascular endothelium of organs plays a key role in the pathogenesis of Plasmodium falciparum malaria. The prevailing hypothesis of why irbc adhere and sequester in tissues is that this acts as a mechanism of avoiding spleen-mediated clearance. Irbc of the rodent parasite Plasmodium berghei ANKA sequester in a fashion analogous to P. falciparum by adhering to the host receptor CD36. To experimentally determine the significance of sequestration for parasite growth, we generated a mutant P. berghei ANKA parasite with a reduced CD36-mediated adherence. Although the cognate parasite ligand binding to CD36 is unknown, we show that nonsequestering parasites have reduced growth and we provide evidence that in addition to avoiding spleen ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602503 Mon, 16 Jan 2012 05:00:00 +0100 5602503 Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection http://www.medworm.com/index.php?rid=5602502&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F77%3Frss%3D1 The signaling adaptor TNFR-associated factor 1 (TRAF1) is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans or lymphocytic choriomeningitis virus (LCMV) clone 13 in mice. In contrast, TRAF1 is maintained at higher levels in virus-specific T cells of HIV controllers or after acute LCMV infection. TRAF1 expression negatively correlates with programmed death 1 expression and HIV load and knockdown of TRAF1 in CD8 T cells from viral controllers results in decreased HIV suppression ex vivo. Consistent with the desensitization of the TRAF1-binding co-stimulatory receptor 4-1BB, 4-1BBL–deficient mice have defects in viral control early, but not late, in chronic infection. TGFβ induces the posttranslational loss of TRAF1, whereas ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602502 Mon, 16 Jan 2012 05:00:00 +0100 5602502 Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence http://www.medworm.com/index.php?rid=5602501&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F61%3Frss%3D1 Vigorous proliferative CD4+ T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4+ T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4+ T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4+ T c... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602501 Mon, 16 Jan 2012 05:00:00 +0100 5602501 Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients http://www.medworm.com/index.php?rid=5602500&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F51%3Frss%3D1 A direct association of islet-autoreactive T cells with β cell destruction in human pancreatic islets from type 1 diabetes (T1D) patients has never been demonstrated, and little is known about disease progression after diagnosis. Frozen pancreas samples were obtained from 45 cadaveric T1D donors with disease durations ranging from 1 wk to >50 yr, 14 nondiabetic controls, 5 nondiabetics with islet autoantibodies, 2 cases of gestational diabetes, and 6 T2D patients. Sections were systematically analyzed for the presence of insulin-sufficient β cells, CD8+ insulitic lesions, and HLA class I hyperexpression. Finally, consecutive sections from HLA-A2–expressing individuals were probed for CD8 T cell reactivity against six defined islet autoantigens associated with T1D by in s... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602500 Mon, 16 Jan 2012 05:00:00 +0100 5602500 A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2 http://www.medworm.com/index.php?rid=5602499&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F35%3Frss%3D1 The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602499 Mon, 16 Jan 2012 05:00:00 +0100 5602499 A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP http://www.medworm.com/index.php?rid=5602498&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F29%3Frss%3D1 A female offspring of consanguineous parents, showed features of Wiskott-Aldrich syndrome (WAS), including recurrent infections, eczema, thrombocytopenia, defective T cell proliferation and chemotaxis, and impaired natural killer cell function. Cells from this patient had undetectable WAS protein (WASP), but normal WAS sequence and messenger RNA levels. WASP interacting protein (WIP), which stabilizes WASP, was also undetectable. A homozygous c.1301C>G stop codon mutation was found in the WIPF1 gene, which encodes WIP. Introduction of WIP into the patient’s T cells restored WASP expression. These findings indicate that WIP deficiency should be suspected in patients with features of WAS in whom WAS sequence and mRNA levels are normal. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602498 Mon, 16 Jan 2012 05:00:00 +0100 5602498 ZBTB1 is a determinant of lymphoid development http://www.medworm.com/index.php?rid=5602497&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F19%3Frss%3D1 In this study, we describe a chemically induced mouse mutation that caused a complete and cell-intrinsic T cell deficiency. Development of other lymphoid lineages was also partially impaired and was severely compromised under competitive conditions. Positional cloning, retroviral transduction, and a somatic reversion event revealed that the causative mutation lay within Zbtb1 (zinc finger and BTB domain containing 1), a gene conserved throughout vertebrate evolution. Our data establish ZBTB1 as a critical determinant of T cell development and lymphopoiesis in general, most likely by acting as a transcriptional regulator. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602497 Mon, 16 Jan 2012 05:00:00 +0100 5602497 RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation http://www.medworm.com/index.php?rid=5602496&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F11%3Frss%3D1 Interleukin 7 (IL-7) promotes pre–B cell survival and proliferation by activating the Pim1 and Akt kinases. These signals must be attenuated to induce G1 cell cycle arrest and expression of the RAG endonuclease, which are both required for IgL chain gene rearrangement. As lost IL-7 signals would limit pre–B cell survival, how cells survive during IgL chain gene rearrangement remains unclear. We show that RAG-induced DNA double-strand breaks (DSBs) generated during IgL chain gene assembly paradoxically promote pre–B cell survival. This occurs through the ATM-dependent induction of Pim2 kinase expression. Similar to Pim1, Pim2 phosphorylates BAD, which antagonizes the pro-apoptotic function of BAX. However, unlike IL-7 induction of Pim1, RAG DSB-mediated induction of Pim2 d... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602496 Mon, 16 Jan 2012 05:00:00 +0100 5602496 A novel neuroprotective therapy for Parkinson's disease using a viral noncoding RNA that protects mitochondrial Complex I activity http://www.medworm.com/index.php?rid=5602495&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F209%2F1%2F1%3Frss%3D1 In this study, we have demonstrated that the administration of a novel noncoding p137 RNA, derived from the human cytomegaloviral β2.7 transcript, can prevent and rescue dopaminergic cell death in vitro and in animal models of PD by protecting mitochondrial Complex I activity. Furthermore, as this p137 RNA is fused to a rabies virus glycoprotein peptide that facilitates delivery of RNA across the blood–brain barrier, such protection can be achieved through a peripheral intravenous administration of this agent after the initiation of a dopaminergic lesion. This approach has major implications for the potential treatment of PD, especially given that this novel agent could have the same protective effect on all diseased neurons affected as part of this disease process, not just the... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5602495 Mon, 16 Jan 2012 05:00:00 +0100 5602495 Human B1 cells are CD3-: A reply to "A human equivalent of mouse B-1 cells?" and "The nature of circulating CD27+CD43+ B cells" http://www.medworm.com/index.php?rid=5531190&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2566%3Frss%3D1 Griffin et al. respond: In the January 2011 issue of the JEM, we identified a population of B cells in human umbilical cord and adult peripheral blood that manifests three key functional features of mouse B1 cells (spontaneous immunoglobulin... (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5531190 Mon, 19 Dec 2011 05:00:00 +0100 5531190 The nature of circulating CD27+CD43+ B cells http://www.medworm.com/index.php?rid=5531189&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2565%3Frss%3D1 To the Editor: We recently read with great interest an article in The Journal of Experimental Medicine from the laboratory of Thomas Rothstein (Griffin et al., 2011). This paper described a new B cell population... (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5531189 Mon, 19 Dec 2011 05:00:00 +0100 5531189 A human equivalent of mouse B-1 cells? http://www.medworm.com/index.php?rid=5531188&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2563%3Frss%3D1 To the Editor: In a recent issue of The Journal of Experimental Medicine, Thomas Rothstein and colleagues, a group with long-standing expertise in the field of mouse B1 cells, reported the description of a B1 B cell... (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5531188 Mon, 19 Dec 2011 05:00:00 +0100 5531188 Cell death and infection: A double-edged sword for host and pathogen survival http://www.medworm.com/index.php?rid=5519444&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2Fi37%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519444 Mon, 19 Dec 2011 05:00:00 +0100 5519444 Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation http://www.medworm.com/index.php?rid=5519443&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2Fi36%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519443 Mon, 19 Dec 2011 05:00:00 +0100 5519443 VPS35 haploinsufficiency increases Alzheimer's disease neuropathology http://www.medworm.com/index.php?rid=5519442&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2Fi35%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519442 Mon, 19 Dec 2011 05:00:00 +0100 5519442 Cell cycle regulation in hematopoietic stem cells http://www.medworm.com/index.php?rid=5519441&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2Fi34%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519441 Mon, 19 Dec 2011 05:00:00 +0100 5519441 Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization http://www.medworm.com/index.php?rid=5519440&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2761%3Frss%3D1 Vol. 208, No. 11, October 24, 2011. Pages 2175–2181. The authors regret that the dosage of RANKL and control antibodies used in the HSC mobilization experiments shown in Figure 6 were incorrectly reported in micrograms. The... (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519440 Mon, 19 Dec 2011 05:00:00 +0100 5519440 Evolutionary genetic dissection of human interferons http://www.medworm.com/index.php?rid=5519439&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2747%3Frss%3D1 Interferons (IFNs) are cytokines that play a key role in innate and adaptive immune responses. Despite the large number of immunological studies of these molecules, the relative contributions of the numerous IFNs to human survival remain largely unknown. Here, we evaluated the extent to which natural selection has targeted the human IFNs and their receptors, to provide insight into the mechanisms that govern host defense in the natural setting. We found that some IFN-α subtypes, such as IFN-α6, IFN-α8, IFN-α13, and IFN-α14, as well as the type II IFN-, have evolved under strong purifying selection, attesting to their essential and nonredundant function in immunity to infection. Conversely, selective constraints have been relaxed for other type I IFNs, particul... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519439 Mon, 19 Dec 2011 05:00:00 +0100 5519439 Immature B cells preferentially switch to IgE with increased direct S{mu} to S{varepsilon} recombination http://www.medworm.com/index.php?rid=5519438&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2733%3Frss%3D1 In this study, we report a role for B cell developmental maturity in IgE CSR. Based in part on a novel flow cytometric IgE CSR assay, we show that immature B cells preferentially switch to IgE versus IgG1 through a mechanism involving increased direct CSR from Cμ to C. Our findings suggest that IgE dysregulation in certain immunodeficiencies may be related to impaired B cell maturation. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519438 Mon, 19 Dec 2011 05:00:00 +0100 5519438 miR-150 regulates the development of NK and iNKT cells http://www.medworm.com/index.php?rid=5519437&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2717%3Frss%3D1 Natural killer (NK) and invariant NK T (iNKT) cells are critical in host defense against pathogens and for the initiation of adaptive immune responses. miRNAs play important roles in NK and iNKT cell development, maturation, and function, but the roles of specific miRNAs are unclear. We show that modulation of miR-150 expression levels has a differential effect on NK and iNKT cell development. Mice with a targeted deletion of miR-150 have an impaired, cell lineage–intrinsic defect in their ability to generate mature NK cells. Conversely, a gain-of-function miR-150 transgene promotes the development of NK cells, which display a more mature phenotype and are more responsive to activation. In contrast, overexpression of miR-150 results in a substantial reduction of iNKT cells in the thy... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519437 Mon, 19 Dec 2011 05:00:00 +0100 5519437 Host innate recognition of an intestinal bacterial pathogen induces TRIF-dependent protective immunity http://www.medworm.com/index.php?rid=5519436&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2705%3Frss%3D1 Toll-like receptor 4 (TLR4), which signals through the adapter molecules myeloid differentiation factor 88 (MyD88) and toll/interleukin 1 receptor domain-containing adapter inducing IFN-β (TRIF), is required for protection against Gram-negative bacteria. TRIF is known to be important in TLR3-mediated antiviral signaling, but the role of TRIF signaling against Gram-negative enteropathogens is currently unknown. We show that TRIF signaling is indispensable for establishing innate protective immunity against Gram-negative Yersinia enterocolitica. Infection of wild-type mice rapidly induced both IFN-β and IFN- in the mesenteric lymph nodes. In contrast, TRIF-deficient mice were defective in these IFN responses and showed impaired phagocytosis in regional macrophages, resulting in gre... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519436 Mon, 19 Dec 2011 05:00:00 +0100 5519436 Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells http://www.medworm.com/index.php?rid=5519435&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2691%3Frss%3D1 Hematopoietic stem cell (HSC) populations change with aging, but the extent to which this is caused by qualitative versus quantitative alterations in HSC subtypes is unclear. Using clonal assays, in this study we show that the aging HSC compartment undergoes both quantitative and qualitative changes. We observed a variable increase of HSC pool size with age, accompanied by the accumulation of predominantly myeloid-biased HSCs that regenerate substantially fewer mature progeny than young myeloid-biased HSCs and exhibit reduced self-renewal activity as measured by long-term secondary transplantation. Old HSCs had a twofold reduction in marrow-homing efficiency and a similar decrease in functional frequency as measured using long-term transplantation assays. Similarly, old HSCs had a twofold ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519435 Mon, 19 Dec 2011 05:00:00 +0100 5519435 A genome-wide RNAi screen in mouse embryonic stem cells identifies Mp1 as a key mediator of differentiation http://www.medworm.com/index.php?rid=5519434&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2675%3Frss%3D1 Despite intense investigation of intrinsic and extrinsic factors that regulate pluripotency, the process of initial fate commitment of embryonic stem (ES) cells is still poorly understood. We used a genome-wide short hairpin RNA screen in mouse ES cells to identify genes that are essential for initiation of differentiation. Knockdown of the scaffolding protein Mek binding protein 1 (Mp1, also known as Lamtor3 or Map2k1ip1) stimulated self-renewal of ES cells, blocked differentiation, and promoted proliferation. Fibroblast growth factor 4 (FGF4) signaling is required for initial fate commitment of ES cells. Knockdown of Mp1 inhibited FGF4-induced differentiation but did not alter FGF4-driven proliferation. This uncoupling of differentiation and proliferation was also observed when oncogenic... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519434 Mon, 19 Dec 2011 05:00:00 +0100 5519434 Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma http://www.medworm.com/index.php?rid=5519433&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2657%3Frss%3D1 In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519433 Mon, 19 Dec 2011 05:00:00 +0100 5519433 Bone morphogenetic protein 7 in dormancy and metastasis of prostate cancer stem-like cells in bone http://www.medworm.com/index.php?rid=5519432&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2641%3Frss%3D1 In this study, we demonstrate that BMP7 (bone morphogenetic protein 7) secreted from bone stromal cells induces senescence in prostate cancer stem-like cells (CSCs) by activating p38 mitogen-activated protein kinase and increasing expression of the cell cycle inhibitor, p21, and the metastasis suppressor gene, NDRG1 (N-myc downstream-regulated gene 1). This effect of BMP7 depended on BMPR2 (BMP receptor 2), and BMPR2 expression inversely correlated with recurrence and bone metastasis in prostate cancer patients. Importantly, this BMP7-induced senescence in CSCs was reversible upon withdrawal of BMP7. Furthermore, treatment of mice with BMP7 significantly suppressed the growth of CSCs in bone, whereas the withdrawal of BMP7 restarted growth of these cells. These results suggest that the BMP... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519432 Mon, 19 Dec 2011 05:00:00 +0100 5519432 CEACAM1 dampens antitumor immunity by down-regulating NKG2D ligand expression on tumor cells http://www.medworm.com/index.php?rid=5519431&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2633%3Frss%3D1 Although carcinoembryonic antigen (CEA)–related cell adhesion molecule 1 (CEACAM1) has been viewed as a tumor suppressor, increasing clinical evidence shows that high levels of CEACAM1 expression on tumors correlates with poor prognosis and high risk of metastasis. Here, we examined the consequences of CEACAM1 expression on tumor cells. We show that tumor cell–associated CEACAM1 causes intracellular retention of various NKG2D ligands in mouse and human tumor cells. CEACAM1-silenced tumor cells expressed more cell surface NKG2D ligands and exhibited greater sensitivity to natural killer cell–mediated cytolysis in vitro and rejection in vivo. Our studies reveal a novel mechanism through which CEACAM1-bearing tumor cells may escape immune-surveillance. (Source: The Journal o... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519431 Mon, 19 Dec 2011 05:00:00 +0100 5519431 Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells http://www.medworm.com/index.php?rid=5519430&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2625%3Frss%3D1 Antibody responses to citrullinated self-proteins are found in autoimmunities, particularly in rheumatoid arthritis, where they serve as a diagnostic indicator. We show here that processing of the protein hen egg-white lysozyme (HEL) resulted in citrullination of peptides presented on class II MHC molecules by antigen-presenting cells. The presentation of the citrullinated peptides but not of the unmodified peptides was associated with autophagy. Dendritic cells (DCs), macrophages, and thymic DCs presented citrullinated peptides constitutively. Their treatment with 3-methyladenine (3MA) blocked presentation of citrullinated HEL peptides, but presentation of unmodified peptides was not affected. Presentation of citrullinated peptides was not detected on B cells or B lymphoma cells under nor... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519430 Mon, 19 Dec 2011 05:00:00 +0100 5519430 TAK1 in brain endothelial cells mediates fever and lethargy http://www.medworm.com/index.php?rid=5519429&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2615%3Frss%3D1 In conclusion, we demonstrate that TAK1 in brain endothelial cells induces COX-2, most likely by activating p38 MAPK and c-Jun, and is necessary for fever and sickness behavior. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519429 Mon, 19 Dec 2011 05:00:00 +0100 5519429 Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome http://www.medworm.com/index.php?rid=5519428&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2607%3Frss%3D1 Epidermal Langerhans cells (LCs) extend dendrites through tight junctions (TJs) to survey the skin surface, but their immunological contribution in vivo remains elusive. We show that LCs were essential for inducing IgG1 responses to patch-immunized ovalbumin in mice that lacked skin dendritic cell subsets. The significance of LC-induced humoral responses was demonstrated in a mouse model of staphylococcal scalded skin syndrome (SSSS), a severe blistering disease in which the desmosomal protein Dsg1 (desmoglein1) is cleaved by Staphylococcus aureus–derived exfoliative toxin (ET). Importantly, ET did not penetrate TJs, and patch immunization did not alter epidermal integrity. Nevertheless, neutralizing anti-ET IgG1 was induced after patch immunization and abolished upon LC depletion, i... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519428 Mon, 19 Dec 2011 05:00:00 +0100 5519428 Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants http://www.medworm.com/index.php?rid=5519427&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2599%3Frss%3D1 Memory B cells (MBCs) and long-lived plasma cells (LLPCs) persist after clearance of infection, yet the specific and nonredundant role MBCs play in subsequent protection is unclear. After resolution of West Nile virus infection in mice, we demonstrate that LLPCs were specific for a single dominant neutralizing epitope, such that immune serum poorly inhibited a variant virus that encoded a mutation at this critical epitope. In contrast, a large fraction of MBC produced antibody that recognized both wild-type (WT) and mutant viral epitopes. Accordingly, antibody produced by the polyclonal pool of MBC neutralized WT and variant viruses equivalently. Remarkably, we also identified MBC clones that recognized the mutant epitope better than the WT protein, despite never having been exposed to the... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519427 Mon, 19 Dec 2011 05:00:00 +0100 5519427 A small CD11b+ human B1 cell subpopulation stimulates T cells and is expanded in lupus http://www.medworm.com/index.php?rid=5519426&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2591%3Frss%3D1 We examined the recently identified human B1 cell population for T cell stimulatory activity. We found two kinds of B1 cells that are distinguished by multiple surface markers and distinct transcriptomic profiles. In both umbilical cord and adult peripheral blood, a CD11b+ subset constitutes ~1 out of every 8–10 B1 cells, whereas a CD11b– subset constitutes the remaining B1 cells. These B1 cell populations differ functionally. CD11b– B1 cells spontaneously secrete much more IgM than CD11b+ B1 cells. In contrast, CD11b+ B1 cells express more CD86, and more efficiently stimulate allogeneic CD4+ T cell expansion, than CD11b– B1 cells. The frequency of these CD11b+ B1 cells is markedly elevated in lupus patients. CD11b+ B1 cells in lupus patients express more CD86 and h... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519426 Mon, 19 Dec 2011 05:00:00 +0100 5519426 A genomic storm in critically injured humans http://www.medworm.com/index.php?rid=5519425&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2581%3Frss%3D1 We describe the circulating leukocyte transcriptome after severe trauma and burn injury, as well as in healthy subjects receiving low-dose bacterial endotoxin, and show that these severe stresses produce a global reprioritization affecting >80% of the cellular functions and pathways, a truly unexpected "genomic storm." In severe blunt trauma, the early leukocyte genomic response is consistent with simultaneously increased expression of genes involved in the systemic inflammatory, innate immune, and compensatory antiinflammatory responses, as well as in the suppression of genes involved in adaptive immunity. Furthermore, complications like nosocomial infections and organ failure are not associated with any genomic evidence of a second hit and differ only in the magnitude and duration of ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519425 Mon, 19 Dec 2011 05:00:00 +0100 5519425 ETV6 mutations in early immature human T cell leukemias http://www.medworm.com/index.php?rid=5519424&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F13%2F2571%3Frss%3D1 In this study, analysis of microarray gene expression signatures in adult T-ALL demonstrated a high prevalence of early immature leukemias and revealed a close relationship between these tumors and myeloid leukemias. Many adult immature T-ALLs harbored mutations in myeloid-specific oncogenes and tumor suppressors including IDH1, IDH2, DNMT3A, FLT3, and NRAS. Moreover, we identified ETV6 mutations as a novel genetic lesion uniquely present in immature adult T-ALL. Our results demonstrate that early immature adult T-ALL represents a heterogeneous category of leukemias characterized by the presence of overlapping myeloid and T-ALL characteristics, and highlight the potential role of ETV6 mutations in these tumors. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5519424 Mon, 19 Dec 2011 05:00:00 +0100 5519424 Remembering Ralph Steinman http://www.medworm.com/index.php?rid=5446306&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2343%3Frss%3D1 As detailed in the Appreciation piece written by Carol Moberg, Ralph’s discovery and investigation of DCs constituted an enormous contribution to immunology. However, Ralph’s influence extended far beyond the strictly scientific. Below, some of Ralph’s closest colleagues and friends reflect on the long-lasting effects of his unwavering mentorship, enthusiasm, generosity, and friendship. Also in this issue is a Perspective, originally commissioned by Ralph and written by Robin Weiss and Peter Vogt. Ralph passed away before he could read this engaging piece, which celebrates the centennial of the publication in the JEM of the Nobel Prize-winning work of Peyton Rous. In addition to their Nobel Prizes, Ralph and Peyton Rous shared the distinctions of being long-time leaders o... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5446306 Mon, 21 Nov 2011 05:00:00 +0100 5446306 An appreciation of Ralph Marvin Steinman (1943-2011) http://www.medworm.com/index.php?rid=5446305&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2337%3Frss%3D1 Ralph Steinman, an editor at the Journal of Experimental Medicine since 1978, shared the 2011 Nobel Prize in Physiology or Medicine for his discovery of dendritic cells (DCs) and their role in immunity. Ralph never knew. He died of pancreatic cancer on September 30, 3 days before the Nobel announcement. Unaware of his death at the time of their announcement, the Nobel Committee made the unprecedented decision that his award would stand. Ralph was the consummate physician-scientist to the end. After his diagnosis, he actively participated in his 4.5 years of treatments, creating experimental therapies using his own DCs in conjunction with the therapies devised by his physicians, all the while traveling, lecturing, and most of all pursuing new investigations in his laboratory. For 38 years&m... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5446305 Mon, 21 Nov 2011 05:00:00 +0100 5446305 Impenetrable barriers or entry portals? The role of cell-cell adhesion during infection http://www.medworm.com/index.php?rid=5436020&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2Fi33%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436020 Mon, 21 Nov 2011 05:00:00 +0100 5436020 A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition http://www.medworm.com/index.php?rid=5436019&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2Fi32%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436019 Mon, 21 Nov 2011 05:00:00 +0100 5436019 Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth http://www.medworm.com/index.php?rid=5436018&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2561%3Frss%3D1 Vol. 208, No. 7, June 13, 2011. Pages 1485–1499. At the request of the Dean for Research, Mayo Clinic Arizona, the paper "Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth" by Zorro-Manrique, et al. is... (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436018 Mon, 21 Nov 2011 05:00:00 +0100 5436018 IGSF4 is a novel TCR {zeta}-chain-interacting protein that enhances TCR-mediated signaling http://www.medworm.com/index.php?rid=5436017&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2545%3Frss%3D1 In this study, we show that IGSF4 directly interacts with the T cell receptor (TCR) -chain and enhances TCR signaling by enhancing -chain phosphorylation. Ectopic overexpression of IGSF4 enhances TCR-mediated T cell activation. In contrast, IGSF4 knockdown shows a dramatic decrease in markers associated with T cell activation compared with those in control small interfering RNA. The transmembrane domain is essential for TCR -chain association and clustering to the immunological synapse, and the ectodomain is associated with T cell interaction with antigen-presenting cells (APCs). IGSF4-deficient mice have impaired TCR-mediated thymocyte selection and maturation. Furthermore, these mice reveal attenuated effector T cell functions accompanied by defective TCR signaling. Collectively, the res... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436017 Mon, 21 Nov 2011 05:00:00 +0100 5436017 MHC class I-specific antibody binding to nonhematopoietic cells drives complement activation to induce transfusion-related acute lung injury in mice http://www.medworm.com/index.php?rid=5436016&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2525%3Frss%3D1 In this study, we confirm the role of reactive oxygen species in the pathogenesis of this mouse model of TRALI and show ultrastructural evidence of pulmonary vascular injury within 5 min of anti–MHC class I mAb injection. However, we demonstrate that disease induction in this model involves macrophages rather than neutrophils or platelets, activation of complement and production of C5a rather than activation of FcRI, FcRIII, or FcRIV, and binding of anti–MHC class I mAb to non-BM–derived cells such as pulmonary vascular endothelium. These observations have important implications for the prevention and treatment of TRALI. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436016 Mon, 21 Nov 2011 05:00:00 +0100 5436016 Chemokines control naive CD8+ T cell selection of optimal lymph node antigen presenting cells http://www.medworm.com/index.php?rid=5436015&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2511%3Frss%3D1 Naive antiviral CD8+ T cells are activated in the draining LN (DLN) by dendritic cells (DCs) presenting viral antigens. However, many viruses infect LN macrophages, which participate in initiation of innate immunity and B cell activation. To better understand how and why T cells select infected DCs rather than macrophages, we performed intravital microscopy and ex vivo analyses after infecting mice with vaccinia virus (VV), a large DNA virus that infects both LN macrophages and DCs. Although CD8+ T cells interact with both infected macrophages and DCs in the LN peripheral interfollicular region (PIR), DCs generate more frequent and stable interactions with T cells. VV infection induces rapid release of CCR5-binding chemokines in the LN, and administration of chemokine-neutralizing antibodi... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436015 Mon, 21 Nov 2011 05:00:00 +0100 5436015 Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers http://www.medworm.com/index.php?rid=5436014&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2497%3Frss%3D1 In this study, we tested the impact of selective FDC ablation on short-term follicle and GC function. Within 2 d of FDC ablation, primary follicles lost their homogeneity and became disorganized bands of cells around T zones. These B cell areas retained CXCL13-expressing stromal cells but often exhibited inappropriate ER-TR7 and CCL21 expression. Ablation of GC FDCs led to the disappearance of GCs. When B cell death was prevented using a Bcl2 transgene, FDC ablation led to splenic GC B cell dispersal. Mesenteric lymph node GCs were more resistant but became dispersed when sphingosine-1-phosphate receptor-2 was also removed. These experiments indicate that FDCs help maintain primary follicles as a B cell exclusive niche and define a critical role for FDCs in cell retention within GCs. (Sour... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436014 Mon, 21 Nov 2011 05:00:00 +0100 5436014 Dendritic cells induce antigen-specific regulatory T cells that prevent graft versus host disease and persist in mice http://www.medworm.com/index.php?rid=5436013&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2489%3Frss%3D1 Foxp3+ regulatory T cells (T reg cells) effectively suppress immunity, but it is not determined if antigen-induced T reg cells (iT reg cells) are able to persist under conditions of inflammation and to stably express the transcription factor Foxp3. We used spleen cells to stimulate the mixed leukocyte reaction (MLR) in the presence of transforming growth factor β (TGF-β) and retinoic acid. We found that the CD11chigh dendritic cell fraction was the most potent at inducing high numbers of alloreactive Foxp3+ cells. The induced CD4+CD25+Foxp3+ cells appeared after extensive proliferation. When purified from the MLR, iT reg cells suppressed both primary and secondary MLR in vitro in an antigen-specific manner. After transfer into allogeneic mice, iT reg cells persisted for 6 mo and ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436013 Mon, 21 Nov 2011 05:00:00 +0100 5436013 In situ induction of dendritic cell-based T cell tolerance in humanized mice and nonhuman primates http://www.medworm.com/index.php?rid=5436012&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2477%3Frss%3D1 In this study, we establish a method of inducing antigen-specific T cell tolerance in situ in diabetic humanized mice and Rhesus monkeys receiving porcine islet xenografts. Antigen-specific T cell tolerance is induced by administration of an antibody ligating a particular epitope on ICAM-1 (intercellular adhesion molecule 1). Antibody-mediated ligation of ICAM-1 on dendritic cells (DCs) led to the arrest of DCs in a semimature stage in vitro and in vivo. Ablation of DCs from mice completely abrogated anti–ICAM-1–induced antigen-specific T cell tolerance. T cell responses to unrelated antigens remained unaffected. In situ induction of DC-mediated T cell tolerance using this method may represent a potent therapeutic tool for preventing graft rejection. (Source: The Journal of Exp... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436012 Mon, 21 Nov 2011 05:00:00 +0100 5436012 Th17 lymphocytes traffic to the central nervous system independently of {alpha}4 integrin expression during EAE http://www.medworm.com/index.php?rid=5436011&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2465%3Frss%3D1 The integrin α4β1 (VLA-4) is used by encephalitogenic T cells to enter the central nervous system (CNS). However, both Th1 and Th17 cells are capable of inducing experimental autoimmune encephalomyelitis (EAE), and the molecular cues mediating the infiltration of Th1 versus Th17 cells into the CNS have not yet been defined. We investigated how blocking of α4 integrins affected trafficking of Th1 and Th17 cells into the CNS during EAE. Although antibody-mediated inhibition of α4 integrins prevented EAE when MOG35-55-specific Th1 cells were adoptively transferred, Th17 cells entered the brain, but not the spinal cord parenchyma, irrespective of α4 blockade. Accordingly, T cell–conditional α4-deficient mice were not resistant to actively induced EAE bu... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436011 Mon, 21 Nov 2011 05:00:00 +0100 5436011 Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic-pituitary-adrenal axis http://www.medworm.com/index.php?rid=5436010&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2449%3Frss%3D1 Skeletal muscle catabolism is a co-morbidity of many chronic diseases and is the result of systemic inflammation. Although direct inflammatory cytokine action on muscle promotes atrophy, nonmuscle sites of action for inflammatory mediators are less well described. We demonstrate that central nervous system (CNS)–delimited interleukin 1β (IL-1β) signaling alone can evoke a catabolic program in muscle, rapidly inducing atrophy. This effect is dependent on hypothalamic–pituitary–adrenal (HPA) axis activation, as CNS IL-1β–induced atrophy is abrogated by adrenalectomy. Furthermore, we identified a glucocorticoid-responsive gene expression pattern conserved in models of acute and chronic inflammatory muscle atrophy. In contrast with studies suggesting that... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436010 Mon, 21 Nov 2011 05:00:00 +0100 5436010 Deregulation of TDP-43 in amyotrophic lateral sclerosis triggers nuclear factor {kappa}B-mediated pathogenic pathways http://www.medworm.com/index.php?rid=5436009&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2429%3Frss%3D1 In this study, we report that TDP-43 and nuclear factor B (NF-B) p65 messenger RNA and protein expression is higher in spinal cords in ALS patients than healthy individuals. TDP-43 interacts with and colocalizes with p65 in glial and neuronal cells from ALS patients and mice expressing wild-type and mutant TDP-43 transgenes but not in cells from healthy individuals or nontransgenic mice. TDP-43 acted as a co-activator of p65, and glial cells expressing higher amounts of TDP-43 produced more proinflammatory cytokines and neurotoxic mediators after stimulation with lipopolysaccharide or reactive oxygen species. TDP-43 overexpression in neurons also increased their vulnerability to toxic mediators. Treatment of TDP-43 mice with Withaferin A, an inhibitor of NF-B activity, reduced denervation ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436009 Mon, 21 Nov 2011 05:00:00 +0100 5436009 Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region http://www.medworm.com/index.php?rid=5436008&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2417%3Frss%3D1 Hematopoietic stem cells (HSCs) emerge during embryogenesis and maintain hematopoiesis in the adult organism. Little is known about the embryonic development of human HSCs. We demonstrate that human HSCs emerge first in the aorta-gonad-mesonephros (AGM) region, specifically in the dorsal aorta, and only later appear in the yolk sac, liver, and placenta. AGM region cells transplanted into immunodeficient mice provide long-term high level multilineage hematopoietic repopulation. Human AGM region HSCs, although present in low numbers, exhibit a very high self-renewal potential. A single HSC derived from the AGM region generates at least 300 daughter HSCs in primary recipients, which disseminate throughout the entire recipient bone marrow and are retransplantable. These findings highlight the ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436008 Mon, 21 Nov 2011 05:00:00 +0100 5436008 Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity http://www.medworm.com/index.php?rid=5436007&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2403%3Frss%3D1 Ecotropic viral integration site 1 (Evi1), a transcription factor of the SET/PR domain protein family, is essential for the maintenance of hematopoietic stem cells (HSCs) in mice and is overexpressed in several myeloid malignancies. Here, we generate reporter mice in which an internal ribosome entry site (IRES)-GFP cassette is knocked-in to the Evi1 locus. Using these mice, we find that Evi1 is predominantly expressed in long-term HSCs (LT-HSCs) in adult bone marrow, and in the hematopoietic stem/progenitor fraction in the aorta-gonad-mesonephros, placenta, and fetal liver of embryos. In both fetal and adult hematopoietic systems, Evi1 expression marks cells with long-term multilineage repopulating activity. When combined with conventional HSC surface markers, sorting according to Evi1 exp... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436007 Mon, 21 Nov 2011 05:00:00 +0100 5436007 Dissociation of VE-PTP from VE-cadherin is required for leukocyte extravasation and for VEGF-induced vascular permeability in vivo http://www.medworm.com/index.php?rid=5436006&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2393%3Frss%3D1 We have recently shown that vascular endothelial protein tyrosine phosphatase (VE-PTP), an endothelial membrane protein, associates with VE-cadherin and is required for optimal VE-cadherin function and endothelial cell contact integrity. The dissociation of VE-PTP from VE-cadherin is triggered by vascular endothelial growth factor (VEGF) and by the binding of leukocytes to endothelial cells in vitro, suggesting that this dissociation is a prerequisite for the destabilization of endothelial cell contacts. Here, we show that VE-cadherin/VE-PTP dissociation also occurs in vivo in response to LPS stimulation of the lung or systemic VEGF stimulation. To show that this dissociation is indeed necessary in vivo for leukocyte extravasation and VEGF-induced vascular permeability, we generated knock-... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436006 Mon, 21 Nov 2011 05:00:00 +0100 5436006 REG-{gamma} associates with and modulates the abundance of nuclear activation-induced deaminase http://www.medworm.com/index.php?rid=5436005&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2385%3Frss%3D1 Activation-induced deaminase (AID) acts on the immunoglobulin loci in activated B lymphocytes to initiate antibody gene diversification. The abundance of AID in the nucleus appears tightly regulated, with most nuclear AID being either degraded or exported back to the cytoplasm. To gain insight into the mechanisms regulating nuclear AID, we screened for proteins interacting specifically with it. We found that REG-, a protein implicated in ubiquitin- and ATP-independent protein degradation, interacts in high stoichiometry with overexpressed nuclear AID as well as with endogenous AID in B cells. REG- deficiency results in increased AID accumulation and increased immunoglobulin class switching. A stable stoichiometric AID–REG- complex can be recapitulated in co-transformed bacteria, and ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436005 Mon, 21 Nov 2011 05:00:00 +0100 5436005 Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion http://www.medworm.com/index.php?rid=5436004&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2375%3Frss%3D1 In this study, we examine the specificity of these two types of T cells. The protein-reactive set recognizes the stretch of residues 13–21 of the insulin B chain. The set reactive to peptide only recognizes the stretch from residues 12–20. A single amino acid shift of the B chain peptide bound to I-Ag7 determines whether T cells recognize peptides generated by the processing of insulin, and consequently their escape from thymic purging. Biochemical experiments indicate that peptides bound in the 13–21 register interact more favorably with I-Ag7 than peptides that bind in the 12–20 register. Thus, self-reactive T cells can become pathogenic in the target organ where high concentrations of antigen and/or differences in intracellular processing present peptides in regi... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436004 Mon, 21 Nov 2011 05:00:00 +0100 5436004 Type I interferon negatively controls plasmacytoid dendritic cell numbers in vivo http://www.medworm.com/index.php?rid=5436003&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2367%3Frss%3D1 In this study, we show that splenic pDCs are reduced in vivo during several systemic viral infections and after administration of synthetic toll-like receptor ligands. We demonstrate that IFN-I, regardless of the source, contributes to this decline and mediates pDC death via the intrinsic apoptosis pathway. These findings demonstrate a feedback control mechanism by which IFN-I modulates pDC numbers, thus fine-tuning systemic IFN-I response to viruses. IFN-I–mediated control of pDCs may explain the loss of pDCs during human infections caused by HBV, HCV, or HIV and has important therapeutic implications for settings in which IFN-I is used to treat infections and autoimmune diseases. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436003 Mon, 21 Nov 2011 05:00:00 +0100 5436003 Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans http://www.medworm.com/index.php?rid=5436002&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2357%3Frss%3D1 Adjuvants are critical for the success of vaccines. Agonists of microbial pattern recognition receptors (PRRs) are promising new adjuvant candidates. A mechanism through which adjuvants enhance immune responses is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double-stranded RNA (polyinosinic:polycytidylic acid [poly IC] stabilized with poly-l-lysine [poly ICLC]), an agonist for toll-like receptor (TLR) 3, and the cytosolic RNA helicase MDA-5. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC, showed up-regulation of genes involved in multiple innate immune pathways in all subjects, including interferon (IFN) and inflammasome signaling. Blocking type I IFN receptor ex vivo significant... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436002 Mon, 21 Nov 2011 05:00:00 +0100 5436002 100 years of Rous sarcoma virus http://www.medworm.com/index.php?rid=5436001&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2351%3Frss%3D1 The discovery of Rous sarcoma virus, which was reported by Peyton Rous in the Journal of Experimental Medicine 100 years ago, opened the field of tumor virology. It showed that some cancers have infectious etiology, led to the discovery of oncogenes, and laid the foundation for the molecular mechanisms of carcinogenesis. Rous spent his entire research career at The Rockefeller Institute, and he was the JEM’s longest serving editor. Here, we comment briefly on the life of this remarkable scientist and on the importance of his discoveries. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436001 Mon, 21 Nov 2011 05:00:00 +0100 5436001 Learning vaccinology from viral infections http://www.medworm.com/index.php?rid=5436000&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F12%2F2347%3Frss%3D1 This issue of the Journal of Experimental Medicine celebrates and honors the life of Ralph Steinman (1943–2011), winner of the 2011 Nobel Prize in Physiology or Medicine. Ralph’s science was rooted in fundamental discovery with the goal of translating these findings into clinical medicine. He recognized the power of immunology in treating human disease and passionately championed studies on vaccine design, immune therapy, and human immunology. One particular collaborative effort between the Steinman and Sekaly laboratories resulted in a paper published in this issue of the journal. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5436000 Mon, 21 Nov 2011 05:00:00 +0100 5436000 p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair http://www.medworm.com/index.php?rid=5353581&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2Fi31%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353581 Mon, 24 Oct 2011 04:00:00 +0100 5353581 Caspase-8 inactivation in T cells increases necroptosis and suppresses autoimmunity in Bim-/- mice http://www.medworm.com/index.php?rid=5353580&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2Fi30%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353580 Mon, 24 Oct 2011 04:00:00 +0100 5353580 Bcl-xL regulates mitochondrial energetics by stabilizing the inner membrane potential http://www.medworm.com/index.php?rid=5353579&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2Fi29%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353579 Mon, 24 Oct 2011 04:00:00 +0100 5353579 The Th17 immune response is controlled by the Rel-ROR{gamma}-ROR{gamma}T transcriptional axis http://www.medworm.com/index.php?rid=5353578&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2321%3Frss%3D1 We report here that c-Rel and RelA/p65 transcription factors drive Th17 differentiation by binding to and activating two distinct Rorg promoters that control RORT and ROR expression, respectively. Similar to RORT, ROR is selectively expressed in Th17 cells and is effective in specifying the Th17 phenotype. T cells deficient in c-Rel or RelA are significantly compromised in Th17 differentiation, and c-Rel–deficient mice are defective in Th17 responses. Thus, Th17 immunity is controlled by a Rel–ROR–RORT axis, and strategies targeting Rel/NF-B can be effective for controlling Th17 cell–mediated diseases. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353578 Mon, 24 Oct 2011 04:00:00 +0100 5353578 DOCK8 deficiency impairs CD8 T cell survival and function in humans and mice http://www.medworm.com/index.php?rid=5353577&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2305%3Frss%3D1 In this study, by analyzing mutant mice and humans, we demonstrate a critical, intrinsic role for DOCK8 in peripheral CD8 T cell survival and function. DOCK8 mutation selectively diminished the abundance of circulating naive CD8 T cells in both species, and in DOCK8-deficient humans, most CD8 T cells displayed an exhausted CD45RA+CCR7– phenotype. Analyses in mice revealed the CD8 T cell abnormalities to be cell autonomous and primarily postthymic. DOCK8 mutant naive CD8 T cells had a shorter lifespan and, upon encounter with antigen on dendritic cells, exhibited poor LFA-1 synaptic polarization and a delay in the first cell division. Although DOCK8 mutant T cells underwent near-normal primary clonal expansion after primary infection with recombinant influenza virus in vivo, they show... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353577 Mon, 24 Oct 2011 04:00:00 +0100 5353577 Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells http://www.medworm.com/index.php?rid=5353576&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2291%3Frss%3D1 Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4–producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4–producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-term... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353576 Mon, 24 Oct 2011 04:00:00 +0100 5353576 Involvement of interleukin-21 in the regulation of colitis-associated colon cancer http://www.medworm.com/index.php?rid=5353575&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2279%3Frss%3D1 Chronic inflammation is a major driving force in the development of cancer in many tissues, but the array of factors involved in this neoplastic transformation are not well understood. We have investigated the role of interleukin (IL)-21 in colitis-associated colon cancer (CAC), as this cytokine is overexpressed in the gut mucosa of patients with ulcerative colitis (UC), a chronic inflammatory disease associated with colon cancer. IL-21 was increased in the gut of patients with UC-associated colon cancer, and in mice with CAC induced by azoxymethane (AOM) and dextran sulfate sodium (DSS). After AOM+DSS treatment, IL-21 KO mice showed reduced mucosal damage, reduced infiltration of T cells, and diminished production of IL-6 and IL-17A. IL-21–deficient mice also developed fewer and sma... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353575 Mon, 24 Oct 2011 04:00:00 +0100 5353575 Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin http://www.medworm.com/index.php?rid=5353574&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2263%3Frss%3D1 In this study, we investigated how Lm specifically targets its receptor on intestinal villi and crosses the intestinal epithelium to disseminate systemically. We demonstrate that Ecad is luminally accessible around mucus-expelling goblet cells (GCs), around extruding enterocytes at the tip and lateral sides of villi, and in villus epithelial folds. We show that upon preferential adherence to accessible Ecad on GCs, Lm is internalized, rapidly transcytosed across the intestinal epithelium, and released in the lamina propria by exocytosis from where it disseminates systemically. Together, these results show that Lm exploits intrinsic tissue heterogeneity to access its receptor and reveal transcytosis as a novel and unanticipated pathway that is hijacked by Lm to breach the intestinal epithel... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353574 Mon, 24 Oct 2011 04:00:00 +0100 5353574 Regulation of neutrophils by interferon-{gamma} limits lung inflammation during tuberculosis infection http://www.medworm.com/index.php?rid=5353573&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2251%3Frss%3D1 Resistance to Mycobacterium tuberculosis requires the host to restrict bacterial replication while preventing an over-exuberant inflammatory response. Interferon (IFN) is crucial for activating macrophages and also regulates tissue inflammation. We dissociate these two functions and show that IFN-–/– memory CD4+ T cells retain their antimicrobial activity but are unable to suppress inflammation. IFN- inhibits CD4+ T cell production of IL-17, which regulates neutrophil recruitment. In addition, IFN- directly inhibits pathogenic neutrophil accumulation in the infected lung and impairs neutrophil survival. Regulation of neutrophils is important because their accumulation is detrimental to the host. We suggest that neutrophilia during tuberculosis indicates failed Th1 immunity or l... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353573 Mon, 24 Oct 2011 04:00:00 +0100 5353573 Initial antibodies binding to HIV-1 gp41 in acutely infected subjects are polyreactive and highly mutated http://www.medworm.com/index.php?rid=5353572&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2237%3Frss%3D1 The initial antibody response to HIV-1 is targeted to envelope (Env) gp41, and is nonneutralizing and ineffective in controlling viremia. To understand the origins and characteristics of gp41-binding antibodies produced shortly after HIV-1 transmission, we isolated and studied gp41-reactive plasma cells from subjects acutely infected with HIV-1. The frequencies of somatic mutations were relatively high in these gp41-reactive antibodies. Reverted unmutated ancestors of gp41-reactive antibodies derived from subjects acutely infected with HIV-1 frequently did not react with autologous HIV-1 Env; however, these antibodies were polyreactive and frequently bound to host or bacterial antigens. In one large clonal lineage of gp41-reactive antibodies, reactivity to HIV-1 Env was acquired only after... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353572 Mon, 24 Oct 2011 04:00:00 +0100 5353572 Critical role of the neutrophil-associated high-affinity receptor for IgE in the pathogenesis of experimental cerebral malaria http://www.medworm.com/index.php?rid=5353571&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2225%3Frss%3D1 The role of the IgE–FcRI complex in malaria severity in Plasmodium falciparum–hosting patients is unknown. We demonstrate that mice genetically deficient for the high-affinity receptor for IgE (FcRIα-KO) or for IgE (IgE-KO) are less susceptible to experimental cerebral malaria (ECM) after infection with Plasmodium berghei (PbANKA). Mast cells and basophils, which are the classical IgE-expressing effector cells, are not involved in disease as mast cell–deficient and basophil-depleted mice developed a disease similar to wild-type mice. However, we show the emergence of an FcRI+ neutrophil population, which is not observed in mice hosting a non–ECM-inducing PbNK65 parasite strain. Depletion of this FcRI+ neutrophil population prevents ECM, whereas transfer of thi... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353571 Mon, 24 Oct 2011 04:00:00 +0100 5353571 A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primates http://www.medworm.com/index.php?rid=5353570&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2217%3Frss%3D1 We describe a live-attenuated vaccine that is safe and efficacious in preventing trachoma in nonhuman primates, a model with excellent predictive value for humans. Cynomolgus macaques infected ocularly with a trachoma strain deficient for the 7.5-kb conserved plasmid presented with short-lived infections that resolved spontaneously without ocular pathology. Multiple infections with the attenuated plasmid-deficient strain produced no inflammatory ocular pathology but induced an anti-chlamydial immune response. Macaques vaccinated with the attenuated strain were either solidly or partially protected after challenge with virulent plasmid-bearing organisms. Partially protected macaques shed markedly less infectious organisms than controls. Immune correlates of protective immunity were not iden... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353570 Mon, 24 Oct 2011 04:00:00 +0100 5353570 XRCC1 suppresses somatic hypermutation and promotes alternative nonhomologous end joining in Igh genes http://www.medworm.com/index.php?rid=5353569&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2209%3Frss%3D1 Activation-induced deaminase (AID) deaminates cytosine to uracil in immunoglobulin genes. Uracils in DNA can be recognized by uracil DNA glycosylase and abasic endonuclease to produce single-strand breaks. The breaks are repaired either faithfully by DNA base excision repair (BER) or mutagenically to produce somatic hypermutation (SHM) and class switch recombination (CSR). To unravel the interplay between repair and mutagenesis, we decreased the level of x-ray cross-complementing 1 (XRCC1), a scaffold protein involved in BER. Mice heterozygous for XRCC1 showed a significant increase in the frequencies of SHM in Igh variable regions in Peyer’s patch cells, and of double-strand breaks in the switch regions during CSR. Although the frequency of CSR was normal in Xrcc1+/– splenic B... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353569 Mon, 24 Oct 2011 04:00:00 +0100 5353569 The requirements for natural Th17 cell development are distinct from those of conventional Th17 cells http://www.medworm.com/index.php?rid=5353568&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2201%3Frss%3D1 In this study, we demonstrate that a population of Th17 cells, natural Th17 cells (nTh17 cells), which acquire effector function during development in the thymus before peripheral antigen exposure, shows preferential usage of T cell receptor Vβ3. nTh17 cells are dependent on major histocompatibility complex (MHC) class II for thymic selection, yet unlike conventional CD4+ T cells, MHC class II expression on thymic cortical epithelium is not sufficient for their development, rather expression on medullary epithelium is necessary. Differential signaling requirements for IL-17 priming further distinguish nTh17 from conventional Th17 cells. Collectively, our findings define a Th17 population, poised to rapidly produce cytokines, that is developmentally distinct from conventional Th17 cell... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353568 Mon, 24 Oct 2011 04:00:00 +0100 5353568 Tolerogenic function of Blimp-1 in dendritic cells http://www.medworm.com/index.php?rid=5353567&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2193%3Frss%3D1 This study is of particular interest because a polymorphism of Blimp-1 associates with SLE. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353567 Mon, 24 Oct 2011 04:00:00 +0100 5353567 The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development http://www.medworm.com/index.php?rid=5353566&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2183%3Frss%3D1 In this study, we show that a locus on rat chromosome 9 controls the size of the natural Treg cell compartment. Fine mapping of this locus with interval-specific congenic lines and association experiments using single nucleotide polymorphisms (SNPs) identified a nonsynonymous SNP in the Vav1 gene that leads to the substitution of an arginine by a tryptophan (p.Arg63Trp). This p.Arg63Trp polymorphism is associated with increased proportion and absolute numbers of Treg cells in the thymus and peripheral lymphoid organs, without impacting the size of the Tconv cell compartment. This polymorphism is also responsible for Vav1 constitutive activation, revealed by its tyrosine 174 hyperphosphorylation and increased guanine nucleotide exchange factor activity. Moreover, it induces a marked reducti... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353566 Mon, 24 Oct 2011 04:00:00 +0100 5353566 Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization http://www.medworm.com/index.php?rid=5353565&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2175%3Frss%3D1 Hematopoietic stem cells (HSCs) are maintained in a specific bone marrow (BM) niche in cavities formed by osteoclasts. Osteoclast-deficient mice are osteopetrotic and exhibit closed BM cavities. Osteoclast activity is inversely correlated with hematopoietic activity; however, how osteoclasts and the BM cavity potentially regulate hematopoiesis is not well understood. To investigate this question, we evaluated hematopoietic activity in three osteopetrotic mouse models: op/op, c-Fos-deficient, and RANKL (receptor activator of nuclear factor kappa B ligand)-deficient mice. We show that, although osteoclasts and, by consequence, BM cavities are absent in these animals, hematopoietic stem and progenitor cell (HSPC) mobilization after granulocyte colony-stimulating factor injection was comparabl... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353565 Mon, 24 Oct 2011 04:00:00 +0100 5353565 BCL6-mediated repression of p53 is critical for leukemia stem cell survival in chronic myeloid leukemia http://www.medworm.com/index.php?rid=5353564&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2163%3Frss%3D1 Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353564 Mon, 24 Oct 2011 04:00:00 +0100 5353564 Unraveling the basic biology and clinical significance of the chlamydial plasmid http://www.medworm.com/index.php?rid=5353563&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2159%3Frss%3D1 Chlamydial plasmids are small, highly conserved, nonconjugative, and nonintegrative DNA molecules that are nearly ubiquitous in many chlamydial species, including Chlamydia trachomatis. There has been significant recent progress in understanding chlamydial plasmid participation in host–microbe interactions, disease, and immune responses. Work in mouse model systems and, very recently, in nonhuman primates demonstrates that plasmid-deficient chlamydial strains function as live attenuated vaccines against genital and ocular infections. Collectively, these studies open new avenues of research into developing vaccines against trachoma and sexually transmitted chlamydial infections. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353563 Mon, 24 Oct 2011 04:00:00 +0100 5353563 Assembling defenses against therapy-resistant leukemic stem cells: Bcl6 joins the ranks http://www.medworm.com/index.php?rid=5353562&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F11%2F2155%3Frss%3D1 The resistance of leukemic stem cells in response to targeted therapies such as tyrosine kinase inhibitors (TKIs) relies on the cooperative activity of multiple signaling pathways and molecules, including TGFβ, AKT, and FOXO transcription factors (TFs). B cell lymphoma 6 (BCL6) is a transcriptional repressor whose translocation or mutation is associated with diffuse large BCL. New data now show that BCL6 is critical for the maintenance of leukemias driven by the BCR-ABL translocation (Philadelphia chromosome), suggesting that BCL6 is a novel, targetable member of the complex signaling pathways critical for leukemic stem cell survival. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5353562 Mon, 24 Oct 2011 04:00:00 +0100 5353562 TOR kinase complexes and cell migration http://www.medworm.com/index.php?rid=5256048&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2Fi28%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256048 Mon, 26 Sep 2011 04:00:00 +0100 5256048 DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling http://www.medworm.com/index.php?rid=5256047&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2141%3Frss%3D1 Dendritic cells (DCs) must travel through lymphatics to carry skin antigens into lymph nodes. The processes controlling their mobilization and migration have not been completely delineated. We studied how DCs in live mice respond to skin inflammation, transmigrate through lymphatic endothelium, and propagate in initial lymphatics. At steady state, dermal DCs remain sessile along blood vessels. Inflammation mobilizes them, accelerating their interstitial motility 2.5-fold. CCR7-deficient BMDCs crawl as fast as wild-type DCs but less persistently. We observed discrete depositions of CCL21 complexed with collagen-IV on the basement membrane of initial lymphatics. Activated DCs move directionally toward lymphatics, contact CCL21 puncta, and migrate through portals into the lumen. CCR7-deficien... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256047 Mon, 26 Sep 2011 04:00:00 +0100 5256047 Regulator of calcineurin 1 mediates pathological vascular wall remodeling http://www.medworm.com/index.php?rid=5256046&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2125%3Frss%3D1 Artery wall remodeling, a major feature of diseases such as hypertension, restenosis, atherosclerosis, and aneurysm, involves changes in the tunica media mass that reduce or increase the vessel lumen. The identification of molecules involved in vessel remodeling could aid the development of improved treatments for these pathologies. Angiotensin II (AngII) is a key effector of aortic wall remodeling that contributes to aneurysm formation and restenosis through incompletely defined signaling pathways. We show that AngII induces vascular smooth muscle cell (VSMC) migration and vessel remodeling in mouse models of restenosis and aneurysm. These effects were prevented by pharmacological inhibition of calcineurin (CN) or lentiviral delivery of CN-inhibitory peptides. Whole-genome analysis reveal... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256046 Mon, 26 Sep 2011 04:00:00 +0100 5256046 Airborne lipid antigens mobilize resident intravascular NKT cells to induce allergic airway inflammation http://www.medworm.com/index.php?rid=5256045&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2113%3Frss%3D1 In this study, we demonstrate that NKT cells constitutively accumulate and reside in the microvasculature of the mouse lung. After a single airborne exposure to lipid antigen, they promptly extravasate to orchestrate the formation of peribronchiolar and interstitial lymphohistiocytic granulomas containing numerous eosinophils. Concomitant airborne exposure to ovalbumin (OVA) induces the priming of OVA-specific Th2 cells and IgE antibodies by the same dendritic cell coexpressing CD1d and MHC class II. Although NKT cell activation remains confined to the lipid-exposed lung and draining lymph nodes, Th2 cells recirculate and seed the lung of a parabiotic partner, conferring susceptibility to OVA challenge months after the initial exposure, in a manner independent of NKT cells and CD1d. Thus, ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256045 Mon, 26 Sep 2011 04:00:00 +0100 5256045 E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKC{zeta} http://www.medworm.com/index.php?rid=5256044&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2099%3Frss%3D1 The carboxyl terminus of constitutive heat shock cognate 70 (HSC70)–interacting protein (CHIP, also known as Stub1) is a U box–containing E3 ubiquitin ligase that is important for protein quality control. The role of CHIP in innate immunity is not known. Here, we report that CHIP knockdown inhibits Toll-like receptor (TLR) 4– and TLR9-driven signaling, but not TLR3-driven signaling; proinflammatory cytokine and type 1 interferon (IFN) production; and maturation of antigen-presenting cells, including macrophages and dendritic cells. We demonstrate that CHIP can recruit the tyrosine kinase Src and atypical protein kinase C (PKC) to the TLR complex, thereby leading to activation of IL-1 receptor–associated kinase 1, TANK-binding kinase 1, and IFN regulatory factors 3 a... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256044 Mon, 26 Sep 2011 04:00:00 +0100 5256044 Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity http://www.medworm.com/index.php?rid=5256043&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2083%3Frss%3D1 We report here an autosomal recessive form of complete TLR3 deficiency in a young man who developed HSE in childhood but remained normally resistant to other infections. This patient is compound heterozygous for two loss-of-function TLR3 alleles, resulting in an absence of response to TLR3 activation by polyinosinic-polycytidylic acid (poly(I:C)) and related agonists in his fibroblasts. Moreover, upon infection of the patient’s fibroblasts with HSV-1, the impairment of IFN-β and - production resulted in high levels of viral replication and cell death. In contrast, the patient’s peripheral blood mononuclear cells responded normally to poly(I:C) and to all viruses tested, including HSV-1. Consistently, various TLR3-deficient leukocytes from the patient, including CD14+ and/o... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256043 Mon, 26 Sep 2011 04:00:00 +0100 5256043 Critical role of Bcl11b in suppressor function of T regulatory cells and prevention of inflammatory bowel disease http://www.medworm.com/index.php?rid=5256042&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2069%3Frss%3D1 Dysregulated CD4+ T cell responses and alterations in T regulatory cells (Treg cells) play a critical role in autoimmune diseases, including inflammatory bowel disease (IBD). The current study demonstrates that removal of Bcl11b at the double-positive stage of T cell development or only in Treg cells causes IBD because of proinflammatory cytokine-producing CD4+ T cells infiltrating the colon. Provision of WT Treg cells prevented IBD, demonstrating that alterations in Treg cells are responsible for the disease. Furthermore, Bcl11b-deficient Treg cells had reduced suppressor activity with altered gene expression profiles, including reduced expression of the genes encoding Foxp3 and IL-10, and up-regulation of genes encoding proinflammatory cytokines. Additionally, the absence of Bcl11b alter... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256042 Mon, 26 Sep 2011 04:00:00 +0100 5256042 SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production http://www.medworm.com/index.php?rid=5256041&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2055%3Frss%3D1 Regulatory T cells (Treg cells) maintain immune homeostasis by limiting inflammatory responses. SOCS1 (suppressor of cytokine signaling 1), a negative regulator of cytokine signaling, is necessary for the suppressor functions of Treg cells in vivo, yet detailed mechanisms remain to be clarified. We found that Socs1–/– Treg cells produced high levels of IFN- and rapidly lost Foxp3 when transferred into Rag2–/– mice or cultured in vitro, even though the CNS2 (conserved noncoding DNA sequence 2) in the Foxp3 enhancer region was fully demethylated. Socs1–/– Treg cells showed hyperactivation of STAT1 and STAT3. Because Foxp3 expression was stable and STAT1 activation was at normal levels in Ifn–/–Socs1–/– Treg cells, the restriction of... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256041 Mon, 26 Sep 2011 04:00:00 +0100 5256041 Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance http://www.medworm.com/index.php?rid=5256040&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2043%3Frss%3D1 A paradigm shift in immunology has been the recent discovery of regulatory T cells (T reg cells), of which CD4+Foxp3+ cells are proven as essential to self-tolerance. Using transgenic B6.Foxp3hCD2 mice to isolate and ablate Foxp3+ T reg cells with an anti-hCD2 antibody, we show for the first time that CD4+Foxp3+ cells are crucial for infectious tolerance induced by nonablative anti–T cell antibodies. In tolerant animals, Foxp3+ T reg cells are constantly required to suppress effector T cells still capable of causing tissue damage. Tolerated tissue contains T cells that are capable of rejecting it, but are prevented from doing so by therapeutically induced Foxp3+ T reg cells. Finally, Foxp3+ cells have been confirmed as the critical missing link through which infectious tolerance oper... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256040 Mon, 26 Sep 2011 04:00:00 +0100 5256040 WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity http://www.medworm.com/index.php?rid=5256039&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2033%3Frss%3D1 Patients with the immunodeficiency Wiskott-Aldrich syndrome (WAS) frequently develop systemic autoimmunity. Here, we demonstrate that mutation of the WAS gene results in B cells that are hyperresponsive to B cell receptor and Toll-like receptor (TLR) signals in vitro, thereby promoting a B cell–intrinsic break in tolerance. Whereas this defect leads to autoantibody production in WAS protein–deficient (WASp–/–) mice without overt disease, chimeric mice in which only the B cell lineage lacks WASp exhibit severe autoimmunity characterized by spontaneous germinal center formation, class-switched autoantibodies, renal histopathology, and early mortality. Both T cell help and B cell–intrinsic TLR engagement play important roles in promoting disease in this model, as... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256039 Mon, 26 Sep 2011 04:00:00 +0100 5256039 Megakaryocytes possess a functional intrinsic apoptosis pathway that must be restrained to survive and produce platelets http://www.medworm.com/index.php?rid=5256038&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2017%3Frss%3D1 We examined the effect on megakaryocytes of three agents that activate the intrinsic apoptosis pathway in other cell types: etoposide, staurosporine, and the BH3 mimetic ABT-737. All three triggered mitochondrial damage, caspase activation, and cell death. Deletion of Bak and Bax rendered megakaryocytes resistant to etoposide and ABT-737. In vivo, mice with a Bak–/– Bax–/– hematopoietic system were protected against thrombocytopenia induced by the chemotherapeutic agent carboplatin. Thus, megakaryocytes do not activate the intrinsic pathway to generate platelets; rather, the opposite is true: they must restrain it to survive and progress safely through proplatelet formation and platelet shedding. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256038 Mon, 26 Sep 2011 04:00:00 +0100 5256038 Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8{alpha}+ dendritic cells http://www.medworm.com/index.php?rid=5256037&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F2005%3Frss%3D1 Despite lack of tumor control in many models, spontaneous T cell priming occurs frequently in response to a growing tumor. However, the innate immune mechanisms that promote natural antitumor T cell responses are undefined. In human metastatic melanoma, there was a correlation between a type I interferon (IFN) transcriptional profile and T cell markers in metastatic tumor tissue. In mice, IFN-β was produced by CD11c+ cells after tumor implantation, and tumor-induced T cell priming was defective in mice lacking IFN-α/βR or Stat1. IFN signaling was required in the hematopoietic compartment at the level of host antigen-presenting cells, and selectively for intratumoral accumulation of CD8α+ dendritic cells, which were demonstrated to be essential using Batf3–/&ndas... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256037 Mon, 26 Sep 2011 04:00:00 +0100 5256037 Type I interferon is selectively required by dendritic cells for immune rejection of tumors http://www.medworm.com/index.php?rid=5256036&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F1989%3Frss%3D1 Cancer immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN’s actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN- during cancer immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elim... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256036 Mon, 26 Sep 2011 04:00:00 +0100 5256036 Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells http://www.medworm.com/index.php?rid=5256035&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F1977%3Frss%3D1 Activating mutations in protein tyrosine phosphatase 11 (Ptpn11) have been identified in childhood acute leukemias, in addition to juvenile myelomonocytic leukemia (JMML), which is a myeloproliferative disorder (MPD). It is not clear whether activating mutations of this phosphatase play a causal role in the pathogenesis of acute leukemias. If so, the cell origin of leukemia-initiating stem cells (LSCs) remains to be determined. Ptpn11E76K mutation is the most common and most active Ptpn11 mutation found in JMML and acute leukemias. However, the pathogenic effects of this mutation have not been well characterized. We have created Ptpn11E76K conditional knock-in mice. Global Ptpn11E76K/+ mutation results in early embryonic lethality. Induced knock-in of this mutation in pan hematopoietic cel... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256035 Mon, 26 Sep 2011 04:00:00 +0100 5256035 Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway http://www.medworm.com/index.php?rid=5256034&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F1963%3Frss%3D1 Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256034 Mon, 26 Sep 2011 04:00:00 +0100 5256034 Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells http://www.medworm.com/index.php?rid=5256033&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F1949%3Frss%3D1 We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256033 Mon, 26 Sep 2011 04:00:00 +0100 5256033 Cannabinoid receptor 2 positions and retains marginal zone B cells within the splenic marginal zone http://www.medworm.com/index.php?rid=5256032&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F1941%3Frss%3D1 Specialized B cells residing in the splenic marginal zone (MZ) continuously survey the blood for antigens and are important for immunity to systemic infections. However, the cues that uniquely attract cells to the MZ have not been defined. Previous work demonstrated that mice deficient in cannabinoid receptor 2 (CB2) have decreased numbers of MZ B cells but it has been unclear whether CB2 regulates MZ B cell development or positioning. We show that MZ B cells are highly responsive to the CB2 ligand 2-arachidonylglycerol (2-AG) and that CB2 antagonism rapidly displaces small numbers of MZ B cells to the blood. Antagonism for longer durations depletes MZ B cells from the spleen. In mice deficient in sphingosine-1-phosphate receptor function, CB2 antagonism causes MZ B cell displacement into ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256032 Mon, 26 Sep 2011 04:00:00 +0100 5256032 Hiding the road signs that lead to tumor immunity http://www.medworm.com/index.php?rid=5256031&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F1937%3Frss%3D1 Tumors exploit many strategies to evade T cell–mediated destruction. For example, tumors can prevent T cell infiltration by modifying gene expression in the endothelial cells and pericytes that form their vasculature. New work showing that the T cell–attracting chemokine CCL2 can be posttranslationally modified in the tumor microenvironment adds another mechanism to the already formidable arsenal of immunoevasion tactics used by solid tumors. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256031 Mon, 26 Sep 2011 04:00:00 +0100 5256031 Oncogenic and tumor suppressor functions of Notch in cancer: it's NOTCH what you think http://www.medworm.com/index.php?rid=5256030&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F10%2F1931%3Frss%3D1 Notch signaling is often considered a model hematopoietic proto-oncogene because of its role as the main trigger of T cell acute lymphoblastic leukemia (T-ALL). Although its role in T-ALL is well characterized and further supported by a high frequency of activating NOTCH1 mutations in T-ALL patients, it still remains an open question whether the effects of Notch signaling are causative in other types of cancer, including solid tumors. Growing evidence supported by recent studies unexpectedly shows that Notch signaling can also have a potent tumor suppressor function in both solid tumors and hematological malignancies. We discuss the intriguing possibility that the pleiotropic functions of Notch can be tumor suppressive or oncogenic depending on the cellular context. (Source: The Journal of... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5256030 Mon, 26 Sep 2011 04:00:00 +0100 5256030 Cellular mechanisms of cardiomyopathy http://www.medworm.com/index.php?rid=5173379&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2Fi27%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173379 Sun, 28 Aug 2011 23:00:00 +0100 5173379 NIK signaling in dendritic cells but not in T cells is required for the development of effector T cells and cell-mediated immune responses http://www.medworm.com/index.php?rid=5173378&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1917%3Frss%3D1 The canonical NF-B pathway is a driving force for virtually all aspects of inflammation. Conversely, the role of the noncanonical NF-B pathway and its central mediator NF-B–inducing kinase (NIK) remains poorly defined. NIK has been proposed to be involved in the formation of TH17 cells, and its absence in TH cells renders them incapable of inducing autoimmune responses, suggesting a T cell–intrinsic role for NIK. Upon systematic analysis of NIK function in cell-mediated immunity, we found that NIK signaling is dispensable within CD4+ T cells but played a pivotal role in dendritic cells (DCs). We discovered that NIK signaling is required in DCs to deliver co-stimulatory signals to CD4+ T cells and that DC-restricted expression of NIK is sufficient to restore TH1 and TH17 respons... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173378 Sun, 28 Aug 2011 23:00:00 +0100 5173378 Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1 http://www.medworm.com/index.php?rid=5173377&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1901%3Frss%3D1 Tissue macrophages (Ms) and dendritic cells (DCs) play essential roles in tissue homeostasis and immunity. How these cells are maintained at their characteristic densities in different tissues has remained unclear. Aided by a novel flow cytometric technique for assessing relative rates of blood-borne precursor recruitment, we examined M and DC population dynamics in the pregnant mouse uterus, where rapid tissue growth facilitated a dissection of underlying regulatory mechanisms. We demonstrate how M dynamics, and thus M tissue densities, are locally controlled by CSF-1, a pleiotropic growth factor whose in situ level of activity varied widely between uterine tissue layers. CSF-1 acted in part by inducing M proliferation and in part by stimulating the extravasation of Ly6Chi monocytes (Mos)... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173377 Sun, 28 Aug 2011 23:00:00 +0100 5173377 Constitutive intestinal NF-{kappa}B does not trigger destructive inflammation unless accompanied by MAPK activation http://www.medworm.com/index.php?rid=5173376&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1889%3Frss%3D1 Nuclear factor (NF)-B, activated by IB kinase (IKK), is a key regulator of inflammation, innate immunity, and tissue integrity. NF-B and one of its main activators and transcriptional targets, tumor necrosis factor (TNF), are up-regulated in many inflammatory diseases that are accompanied by tissue destruction. The etiology of many inflammatory diseases is poorly understood, but often depends on genetic factors and environmental triggers that affect NF-B and related pathways. It is unknown, however, whether persistent NF-B activation is sufficient for driving symptomatic chronic inflammation and tissue damage. To address this question, we generated IKKβ(EE)IEC mice, which express a constitutively active form of IKKβ in intestinal epithelial cell (IECs). IKKβ(EE)IEC mice exhi... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173376 Sun, 28 Aug 2011 23:00:00 +0100 5173376 Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells http://www.medworm.com/index.php?rid=5173375&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1875%3Frss%3D1 Human memory T cells (TM cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6+ and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets. We show that common chain (c)–using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6+, but not CCR6–, TM cells, even in CCR6+ cells lacking IL-17 expression ex vivo. Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by c-cytokines, as does ectopic expression of the transcription factors FOXO1 or... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173375 Sun, 28 Aug 2011 23:00:00 +0100 5173375 Preexisting helminth infection induces inhibition of innate pulmonary anti-tuberculosis defense by engaging the IL-4 receptor pathway http://www.medworm.com/index.php?rid=5173374&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1863%3Frss%3D1 Tuberculosis and helminthic infections coexist in many parts of the world, yet the impact of helminth-elicited Th2 responses on the ability of the host to control Mycobacterium tuberculosis (Mtb) infection has not been fully explored. We show that mice infected with the intestinal helminth Nippostrongylus brasiliensis (Nb) exhibit a transitory impairment of resistance to airborne Mtb infection. Furthermore, a second dose of Nb infection substantially increases the bacterial burden in the lungs of co-infected mice. Interestingly, the Th2 response in the co-infected animals did not impair the onset and development of the protective Mtb-specific Th1 cellular immune responses. However, the helminth-induced Th2 environment resulted in the accumulation of alternatively activated macrophages (AAM... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173374 Sun, 28 Aug 2011 23:00:00 +0100 5173374 Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss http://www.medworm.com/index.php?rid=5173373&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1849%3Frss%3D1 IL-20 is a proinflammatory cytokine of the IL-10 family that is involved in psoriasis, rheumatoid arthritis, atherosclerosis, and stroke. However, little is known about the role of IL-20 in bone destruction. We explored the function of IL-20 in osteoclastogenesis and the therapeutic potential of anti–IL-20 monoclonal antibody 7E for treating osteoporosis. Higher serum IL-20 levels were detected in patients with osteopenia and osteoporosis and in ovariectomized (OVX) mice. IL-20 mediates osteoclastogenesis by up-regulating the receptor activator of NF-B (RANK) expression in osteoclast precursor cells and RANK ligand (RANKL) in osteoblasts. 7E treatment completely inhibited osteoclast differentiation induced by macrophage colony-stimulating factor (M-CSF) and RANKL in vitro and protect... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173373 Sun, 28 Aug 2011 23:00:00 +0100 5173373 Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice http://www.medworm.com/index.php?rid=5173372&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1835%3Frss%3D1 Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173372 Sun, 28 Aug 2011 23:00:00 +0100 5173372 Extracellular ATP acts on P2Y2 purinergic receptors to facilitate HIV-1 infection http://www.medworm.com/index.php?rid=5173371&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1823%3Frss%3D1 We report that ATP is released from HIV-1 target cells through pannexin-1 channels upon interaction between the HIV-1 envelope protein and specific target cell receptors. Extracellular ATP then acts on purinergic receptors, including P2Y2, to activate proline-rich tyrosine kinase 2 (Pyk2) kinase and transient plasma membrane depolarization, which in turn stimulate fusion between Env-expressing membranes and membranes containing CD4 plus appropriate chemokine co-receptors. Inhibition of any of the constituents of this cascade (pannexin-1, ATP, P2Y2, and Pyk2) impairs the replication of HIV-1 mutant viruses that are resistant to conventional antiretroviral agents. Altogether, our results reveal a novel signaling pathway involved in the early steps of HIV-1 infection that may be targeted with... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173371 Sun, 28 Aug 2011 23:00:00 +0100 5173371 High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling http://www.medworm.com/index.php?rid=5173370&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1809%3Frss%3D1 T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of immature T cells that often shows aberrant activation of Notch1 and PI3K–Akt pathways. Although mutations that activate PI3K–Akt signaling have previously been identified, the relative contribution of growth factor-dependent activation is unclear. We show here that pharmacologic inhibition or genetic deletion of insulin-like growth factor 1 receptor (IGF1R) blocks the growth and viability of T-ALL cells, whereas moderate diminution of IGF1R signaling compromises leukemia-initiating cell (LIC) activity as defined by transplantability in syngeneic/congenic secondary recipients. Furthermore, IGF1R is a Notch1 target, and Notch1 signaling is required to maintain IGF1R expression at high levels in T-ALL cells. Th... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173370 Sun, 28 Aug 2011 23:00:00 +0100 5173370 Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma http://www.medworm.com/index.php?rid=5173369&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1799%3Frss%3D1 New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173369 Sun, 28 Aug 2011 23:00:00 +0100 5173369 CD103+ pulmonary dendritic cells preferentially acquire and present apoptotic cell-associated antigen http://www.medworm.com/index.php?rid=5173368&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1789%3Frss%3D1 In this study, we show that only CD103+ DCs were able to acquire and transport apoptotic cells to the draining LNs and cross present apoptotic cell–associated antigen to CD8 T cells. In contrast, both the CD11bhi and the CD103+ DCs were able to ingest and traffic latex beads or soluble antigen. CD103+ DCs selectively exhibited high expression of TLR3, and ligation of this receptor led to enhanced in vivo cytotoxic T cell responses to apoptotic cell–associated antigen. The selective role for CD103+ DCs was confirmed in Batf3–/– mice, which lack this DC subtype. Our findings suggest that CD103+ DCs are the DC subset in the lung that captures and presents apoptotic cell–associated antigen under homeostatic and inflammatory conditions and raise the possibility for... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173368 Sun, 28 Aug 2011 23:00:00 +0100 5173368 Differential regulation of mast cell degranulation versus cytokine secretion by the actin regulatory proteins Coronin1a and Coronin1b http://www.medworm.com/index.php?rid=5173367&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1777%3Frss%3D1 In this study, we provide genetic evidence for a critical role of the actin-regulatory proteins Coronin1a (Coro1a) and Coro1b on exocytic pathways in MCs: Coro1a–/– bone marrow–derived MCs exhibit increased FcRI-mediated degranulation of secretory lysosomes but significantly reduced secretion of cytokines. Hyperdegranulation of Coro1a–/– MCs is further augmented by the additional loss of Coro1b. In vivo, Coro1a–/–Coro1b–/– mice displayed enhanced passive cutaneous anaphylaxis. Functional reconstitution assays revealed that the inhibitory effect of Coro1a on MC degranulation strictly correlates with cortical localization of Coro1a, requires its filamentous actin–binding activity, and is regulated by phosphorylation of Ser2 of Coro1... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173367 Sun, 28 Aug 2011 23:00:00 +0100 5173367 A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity http://www.medworm.com/index.php?rid=5173366&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1767%3Frss%3D1 It is known that vitamin A and its metabolite, retinoic acid (RA), are essential for host defense. However, the mechanisms for how RA controls inflammation are incompletely understood. The findings presented in this study show that RA signaling occurs concurrent with the development of inflammation. In models of vaccination and allogeneic graft rejection, whole body imaging reveals that RA signaling is temporally and spatially restricted to the site of inflammation. Conditional ablation of RA signaling in T cells significantly interferes with CD4+ T cell effector function, migration, and polarity. These findings provide a new perspective of the role of RA as a mediator directly controlling CD4+ T cell differentiation and immunity. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173366 Sun, 28 Aug 2011 23:00:00 +0100 5173366 The Paf oncogene is essential for hematopoietic stem cell function and development http://www.medworm.com/index.php?rid=5173365&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1757%3Frss%3D1 Hematopoietic stem cells (HSCs) self-renew to maintain the lifelong production of all blood populations. Here, we show that the proliferating cell nuclear antigen–associated factor (Paf) is highly expressed in cycling bone marrow HSCs and plays a critical role in hematopoiesis. Mice lacking Paf exhibited reduced bone marrow cellularity; reduced numbers of HSCs and committed progenitors; and leukopenia. These phenotypes are caused by a cell-intrinsic blockage in the development of long-term (LT)-HSCs into multipotent progenitors and preferential loss of lymphoid progenitors caused by markedly increased p53-mediated apoptosis. In addition, LT-HSCs from Paf–/– mice had increased levels of reactive oxygen species (ROS), failed to maintain quiescence, and were unable to suppor... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173365 Sun, 28 Aug 2011 23:00:00 +0100 5173365 Loss of Roquin induces early death and immune deregulation but not autoimmunity http://www.medworm.com/index.php?rid=5173364&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1749%3Frss%3D1 In this study, we demonstrate that tissue-specific ablation of Roquin in T or B cells, in the entire hematopoietic system, or in epithelial cells of transplanted thymi did not cause autoimmunity. Loss of Roquin induced elevated expression of ICOS through T cell–intrinsic and –extrinsic mechanisms, which itself was not sufficient to break self-tolerance. Instead, ablation of Roquin in the hematopoietic system caused defined changes in immune homeostasis, including the expansion of macrophages, eosinophils, and T cell subsets, most dramatically CD8 effector–like T cells, through cell-autonomous and nonautonomous mechanisms. Germline Roquin deficiency led to perinatal lethality, which was partially rescued on the genetic background of an outbred strain. However, not even com... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173364 Sun, 28 Aug 2011 23:00:00 +0100 5173364 CD1b tetramers bind {alpha}{beta} T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans http://www.medworm.com/index.php?rid=5173363&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F9%2F1741%3Frss%3D1 Microbial lipids activate T cells by binding directly to CD1 and T cell receptors (TCRs) or by indirect effects on antigen-presenting cells involving induction of lipid autoantigens, CD1 transcription, or cytokine release. To distinguish among direct and indirect mechanisms, we developed fluorescent human CD1b tetramers and measured T cell staining. CD1b tetramer staining of T cells requires glucose monomycolate (GMM) antigens, is specific for TCR structure, and is blocked by a recombinant clonotypic TCR comprised of TRAV17 and TRBV4-1, proving that CD1b–glycolipid complexes bind the TCR. GMM-loaded tetramers brightly stain a small subpopulation of blood-derived cells from humans infected with Mycobacterium tuberculosis, providing direct detection of a CD1b-reactive T cell repertoire... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5173363 Sun, 28 Aug 2011 23:00:00 +0100 5173363 Osteoblast mineralization requires b1 integrin/ICAP-1-dependent fibronectin deposition http://www.medworm.com/index.php?rid=5084388&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2Fi26%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084388 Sun, 31 Jul 2011 23:00:00 +0100 5084388 A cell-autonomous requirement for neutral sphingomyelinase 2 in bone mineralization http://www.medworm.com/index.php?rid=5084387&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2Fi25%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084387 Sun, 31 Jul 2011 23:00:00 +0100 5084387 Nuclear translocation of AMPK-a1 potentiates striatal neurodegeneration in Huntington's disease http://www.medworm.com/index.php?rid=5084386&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2Fi24%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084386 Sun, 31 Jul 2011 23:00:00 +0100 5084386 Sumoylation inhibits a-synuclein aggregation and toxicity http://www.medworm.com/index.php?rid=5084385&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2Fi23%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084385 Sun, 31 Jul 2011 23:00:00 +0100 5084385 Anaplasma phagocytophilum induces actin phosphorylation to selectively regulate gene transcription in Ixodes scapularis ticks http://www.medworm.com/index.php?rid=5084384&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1737%3Frss%3D1 Vol. 207, No. 8, August 2, 2010. Pages 1727–1743. Following the print publication of this article, the authors noted that an acknowledgment of the support given by Lesley Bell-Sakyi (University of Edinburgh) had been inadvertently omitted.... (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084384 Sun, 31 Jul 2011 23:00:00 +0100 5084384 Cortactin deficiency is associated with reduced neutrophil recruitment but increased vascular permeability in vivo http://www.medworm.com/index.php?rid=5084383&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1721%3Frss%3D1 In this study, we analyzed in vivo whether these processes require the function of the actin nucleation–promoting factor cortactin. Basal vascular permeability for high molecular weight substances was enhanced in cortactin-deficient mice. Despite this leakiness, neutrophil extravasation in the tumor necrosis factor–stimulated cremaster was inhibited by the loss of cortactin. The permeability defect was caused by reduced levels of activated Rap1 (Ras-related protein 1) in endothelial cells and could be rescued by activating Rap1 via the guanosine triphosphatase (GTPase) exchange factor EPAC (exchange protein directly activated by cAMP). The defect in neutrophil extravasation was caused by enhanced rolling velocity and reduced adhesion in postcapillary venules. Impaired rolling i... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084383 Sun, 31 Jul 2011 23:00:00 +0100 5084383 Epithelial transglutaminase 2 is needed for T cell interleukin-17 production and subsequent pulmonary inflammation and fibrosis in bleomycin-treated mice http://www.medworm.com/index.php?rid=5084382&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1707%3Frss%3D1 Pulmonary fibrosis is a potentially life-threatening disease that may be caused by overt or asymptomatic inflammatory responses. However, the precise mechanisms by which tissue injury is translated into inflammation and consequent fibrosis remain to be established. Here, we show that in a lung injury model, bleomycin induced the secretion of IL-6 by epithelial cells in a transglutaminase 2 (TG2)–dependent manner. This response represents a key step in the differentiation of IL-17–producing T cells and subsequent inflammatory amplification in the lung. The essential role of epithelial cells, but not inflammatory cells, TG2 was confirmed in bone marrow chimeras; chimeras made in TG2-deficient recipients showed reduced inflammation and fibrosis, compared with those in wild-type mi... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084382 Sun, 31 Jul 2011 23:00:00 +0100 5084382 Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain http://www.medworm.com/index.php?rid=5084381&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1695%3Frss%3D1 In this study, starting with the criterion of Flt3 (FMS-like receptor tyrosine kinase 3)-dependent development, we characterize the features of authentic DCs within the meninges and choroid plexus in healthy mouse brains. Analyses of morphology, gene expression, and antigen-presenting function established a close relationship between meningeal and choroid plexus DCs (m/chDCs) and spleen DCs. DCs in both sites shared an intrinsic requirement for Flt3 ligand. Microarrays revealed differences in expression of transcripts encoding surface molecules, transcription factors, pattern recognition receptors, and other genes in m/chDCs compared with monocytes and microglia. Migrating pre-DC progenitors from bone marrow gave rise to m/chDCs that had a 5–7-d half-life. In contrast to microglia, D... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084381 Sun, 31 Jul 2011 23:00:00 +0100 5084381 Tissue-specific expression of B7x protects from CD4 T cell-mediated autoimmunity http://www.medworm.com/index.php?rid=5084380&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1683%3Frss%3D1 B7x, an inhibitory member of the B7/CD28 superfamily, is highly expressed in a broad range of nonhematopoietic organs, suggesting a role in maintaining peripheral tolerance. As endogenous B7x protein is expressed in pancreatic islets, we investigated whether the molecule inhibits diabetogenic responses. Transfer of disease-inducing BDC2.5 T cells into B7x-deficient mice resulted in a more aggressive form of diabetes than in wild-type animals. This exacerbation of disease correlated with higher frequencies of islet-infiltrating Th1 and Th17 cells. Conversely, local B7x overexpression inhibited the development of autoimmunity, as crossing diabetes-susceptible BDC2.5/B6g7 mice to animals overexpressing B7x in pancreatic islets abrogated disease induction. This protection was caused by the inh... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084380 Sun, 31 Jul 2011 23:00:00 +0100 5084380 B cells enhance early innate immune responses during bacterial sepsis http://www.medworm.com/index.php?rid=5084379&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1673%3Frss%3D1 This study identifies a novel role for IFN-I–activated B cells in protective early innate immune responses during bacterial sepsis. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084379 Sun, 31 Jul 2011 23:00:00 +0100 5084379 The immunoreceptor adapter protein DAP12 suppresses B lymphocyte-driven adaptive immune responses http://www.medworm.com/index.php?rid=5084378&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1661%3Frss%3D1 DAP12, an immunoreceptor tyrosine-based activation motif–bearing adapter protein, is involved in innate immunity mediated by natural killer cells and myeloid cells. We show that DAP12-deficient mouse B cells and B cells from a patient with Nasu-Hakola disease, a recessive genetic disorder resulting from loss of DAP12, showed enhanced proliferation after stimulation with anti-IgM or CpG. Myeloid-associated immunoglobulin-like receptor (MAIR) II (Cd300d) is a DAP12-associated immune receptor. Like DAP12-deficient B cells, MAIR-II–deficient B cells were hyperresponsive. Expression of a chimeric receptor composed of the MAIR-II extracellular domain directly coupled to DAP12 into the DAP12-deficient or MAIR-II–deficient B cells suppressed B cell receptor (BCR)–mediated p... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084378 Sun, 31 Jul 2011 23:00:00 +0100 5084378 Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination http://www.medworm.com/index.php?rid=5084377&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1649%3Frss%3D1 In this study, we show that during CSR, AID forms a complex with KAP1 (KRAB domain–associated protein 1) and HP1 (heterochromatin protein 1) that is tethered to the donor switch region (Sµ) bearing H3K9me3 (trimethylated histone H3 at lysine 9) in vivo. Furthermore, in vivo disruption of this complex results in impaired AID recruitment to Sµ, inefficient DSB formation, and a concomitant defect in CSR but not in somatic hypermutation. We propose that KAP1 and HP1 tether AID to H3K9me3 residues at the donor switch region, thus providing a mechanism linking AID to epigenetic modifications during CSR. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084377 Sun, 31 Jul 2011 23:00:00 +0100 5084377 Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis http://www.medworm.com/index.php?rid=5084376&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1635%3Frss%3D1 Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-, IFN-, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dep... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084376 Sun, 31 Jul 2011 23:00:00 +0100 5084376 Inflammatory chemokine receptors regulate CD8+ T cell contraction and memory generation following infection http://www.medworm.com/index.php?rid=5084375&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1621%3Frss%3D1 In this study, we describe a novel role for the chemokine receptors CCR5 and CXCR3 in regulating effector CD8+ T cell contraction and memory generation after influenza virus infection. We find that Ccr5–/– Cxcr3–/– cells show markedly decreased contraction after viral clearance, leading to the establishment of massive numbers of memory CD8+ T cells. Ccr5–/– Cxcr3–/– cells show reduced expression of CD69 in the lung during the peak of infection, which coincides with differential localization and the rapid appearance of memory precursor cells. Analysis of single chemokine receptor–deficient cells revealed that CXCR3 is primarily responsible for this phenotype, although there is also a role for CCR5 in the enhancement of T cell memory. The... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084375 Sun, 31 Jul 2011 23:00:00 +0100 5084375 Chemokine receptor CXCR3 facilitates CD8+ T cell differentiation into short-lived effector cells leading to memory degeneration http://www.medworm.com/index.php?rid=5084374&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1605%3Frss%3D1 Strength of inflammatory stimuli during the early expansion phase plays a crucial role in the effector versus memory cell fate decision of CD8+ T cells. But it is not known how early lymphocyte distribution after infection has an impact on this process. We demonstrate that the chemokine receptor CXCR3 is involved in promoting CD8+ T cell commitment to an effector fate rather than a memory fate by regulating T cell recruitment to an antigen/inflammation site. After systemic viral or bacterial infection, the contraction of CXCR3–/– antigen-specific CD8+ T cells is significantly attenuated, resulting in massive accumulation of fully functional memory CD8+ T cells. Early after infection, CXCR3–/– antigen-specific CD8+ T cells fail to cluster at the marginal zone in the ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084374 Sun, 31 Jul 2011 23:00:00 +0100 5084374 Pten mediates Myc oncogene dependence in a conditional zebrafish model of T cell acute lymphoblastic leukemia http://www.medworm.com/index.php?rid=5084373&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1595%3Frss%3D1 The MYC oncogenic transcription factor is overexpressed in most human cases of T cell acute lymphoblastic leukemia (T-ALL), often downstream of mutational NOTCH1 activation. Genetic alterations in the PTEN–PI3K–AKT pathway are also common in T-ALL. We generated a conditional zebrafish model of T-ALL in which 4-hydroxytamoxifen (4HT) treatment induces MYC activation and disease, and withdrawal of 4HT results in T-ALL apoptosis and tumor regression. However, we found that loss-of-function mutations in zebrafish pten genes, or expression of a constitutively active Akt2 transgene, rendered tumors independent of the MYC oncogene and promoted disease progression after 4HT withdrawal. Moreover, MYC suppresses pten mRNA levels, suggesting that Akt pathway activation downstream of MYC p... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084373 Sun, 31 Jul 2011 23:00:00 +0100 5084373 Genomic loss of the putative tumor suppressor gene E2A in human lymphoma http://www.medworm.com/index.php?rid=5084372&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1585%3Frss%3D1 In this study, we describe a recurrent E2A gene deletion in at least 70% of patients with Sézary syndrome (SS), a subtype of T cell lymphoma. Loss of E2A results in enhanced proliferation and cell cycle progression via derepression of the protooncogene MYC and the cell cycle regulator CDK6. Furthermore, by examining the gene expression profile of SS cells after restoration of E2A expression, we identify several E2A-regulated genes that interfere with oncogenic signaling pathways, including the Ras pathway. Several of these genes are down-regulated or lost in primary SS tumor cells. These data demonstrate a tumor suppressor function of E2A in human lymphoid cells and could help to develop new treatment strategies for human lymphomas with altered E2A activity. (Source: The Journal of ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084372 Sun, 31 Jul 2011 23:00:00 +0100 5084372 Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3-deficient mice http://www.medworm.com/index.php?rid=5084371&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1579%3Frss%3D1 Our previous studies have implicated signaling through the tumor necrosis family receptors OX40 and CD30 as critical for maintaining CD4 memory responses. We show that signals through both molecules are also required for CD4 effector-mediated autoimmune tissue damage. Under normal circumstances, male mice deficient in the forkhead transcription factor FoxP3, which lack regulatory CD4 T cells, develop lethal autoimmune disease in the first few weeks of life. However, in the combined absence of OX40 and CD30, FoxP3-deficient mice develop normally and breed successfully. The extensive tissue infiltration and organ destruction characteristic of FoxP3 disease does not appear in these mice, and their mortality is not associated with autoimmunity. Although the absence of OX40 plays the dominant r... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084371 Sun, 31 Jul 2011 23:00:00 +0100 5084371 IFN-{gamma}- and IL-10-expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis http://www.medworm.com/index.php?rid=5084370&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1571%3Frss%3D1 Foxp3+ CD4 regulatory T cells (T reg cells) are important in limiting immunopathology in infections. However, identifying pathogen-specific epitopes targeted by these cells has been elusive. Using MHC class II/peptide tetramers and intracellular cytokine staining, we identify T reg cells recognizing two virus-specific CD4 T cell epitopes in the coronavirus-infected central nervous system as well as naive T cell precursor pools. These T reg cells are detected at the same time as effector T cells (T eff cells) exhibiting the same specificity and can suppress T eff cell proliferation after stimulation with cognate peptide. These virus-specific T reg cells may be especially effective in inhibiting the immune response during the peak of infection, when virus antigen is maximal. Furthermore, the... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084370 Sun, 31 Jul 2011 23:00:00 +0100 5084370 Tumor necrosis factor restricts hematopoietic stem cell activity in mice: involvement of two distinct receptors http://www.medworm.com/index.php?rid=5084369&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F8%2F1563%3Frss%3D1 Whereas maintenance of hematopoietic stem cells (HSCs) is a requisite for life, uncontrolled expansion of HSCs might enhance the propensity for leukemic transformation. Accordingly, HSC numbers are tightly regulated. The identification of physical cellular HSC niches has underscored the importance of extrinsic regulators of HSC homeostasis. However, whereas extrinsic positive regulators of HSCs have been identified, opposing extrinsic repressors of HSC expansion in vivo have yet to be described. Like many other acute and chronic inflammatory diseases, bone marrow (BM) failure syndromes are associated with tumor necrosis factor-α (TNF) overexpression. However, the in vivo relevance of TNF in the regulation of HSCs has remained unclear. Of considerable relevance for normal hematopoiesi... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=5084369 Sun, 31 Jul 2011 23:00:00 +0100 5084369 SPARC promotes pericyte recruitment via inhibition of endoglin-dependent TGF-b1 activity http://www.medworm.com/index.php?rid=4996718&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2Fi22%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996718 Sun, 03 Jul 2011 23:00:00 +0100 4996718 Pannexin 3 functions as an ER Ca2+ channel, hemichannel, and gap junction to promote osteoblast differentiation http://www.medworm.com/index.php?rid=4996717&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2Fi21%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996717 Sun, 03 Jul 2011 23:00:00 +0100 4996717 Tinman/Nkx2-5 acts via miR-1 and upstream of Cdc42 to regulate heart function across species http://www.medworm.com/index.php?rid=4996716&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2Fi20%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996716 Sun, 03 Jul 2011 23:00:00 +0100 4996716 Type XII collagen regulates osteoblast polarity and communication during bone formation http://www.medworm.com/index.php?rid=4996715&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2Fi19%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996715 Sun, 03 Jul 2011 23:00:00 +0100 4996715 Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii http://www.medworm.com/index.php?rid=4996714&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2F1547%3Frss%3D1 Apicomplexa are important pathogens that include the causative agents of malaria, toxoplasmosis, and cryptosporidiosis. Apicomplexan parasites contain a relict chloroplast, the apicoplast. The apicoplast is indispensable and an attractive drug target. The apicoplast is home to a 1-deoxy-d-xylulose-5-phosphate (DOXP) pathway for the synthesis of isoprenoid precursors. This pathway is believed to be the most conserved function of the apicoplast, and fosmidomycin, a specific inhibitor of the pathway, is an effective antimalarial. Surprisingly, fosmidomycin has no effect on most other apicomplexans. Using Toxoplasma gondii, we establish that the pathway is essential in parasites that are highly fosmidomycin resistant. We define the molecular basis of resistance and susceptibility, experimental... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996714 Sun, 03 Jul 2011 23:00:00 +0100 4996714 ATF6{beta} is a host cellular target of the Toxoplasma gondii virulence factor ROP18 http://www.medworm.com/index.php?rid=4996713&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2F1533%3Frss%3D1 In this study, we show that ROP18 targets the host endoplasmic reticulum–bound transcription factor ATF6β. Disruption of the ROP18 gene severely impairs acute toxoplasmosis by the type I RH strain. Because another virulence factor ROP16 kinase modulates immune responses through its N-terminal portion, we focus on the role of the N terminus of ROP18 in the subversion of host cellular functions. The N-terminal extension of ROP18 contributes to ATF6β-dependent pathogenicity by interacting with ATF6β and destabilizing it. The kinase activity of ROP18 is essential for proteasome-dependent degradation of ATF6β and for parasite virulence. Consistent with a key role for ATF6β in resistance against this intracellular pathogen, ATF6β-deficient mice exhibit a high ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996713 Sun, 03 Jul 2011 23:00:00 +0100 4996713 SOCS2 regulates T helper type 2 differentiation and the generation of type 2 allergic responses http://www.medworm.com/index.php?rid=4996712&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2F1523%3Frss%3D1 We report that SOCS2–/– CD4+ T cells show markedly enhanced Th2 differentiation. SOCS2–/– mice, as well as RAG-1–/– mice transferred with SOCS2–/– CD4+ T cells, exhibit elevated type 2 responses after helminth antigen challenge. Moreover, in in vivo models of atopic dermatitis and allergen-induced airway inflammation, SOCS2–/– mice show significantly elevated IgE, eosinophilia, type 2 responses, and inflammatory pathology relative to wild-type mice. Finally, after T cell activation, markedly enhanced STAT6 and STAT5 phosphorylation is observed in SOCS2–/– T cells, whereas STAT3 phosphorylation is blunted. Thus, we provide the first evidence that SOCS2 plays an important role in regulating Th2 cell expansion and develop... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996712 Sun, 03 Jul 2011 23:00:00 +0100 4996712 The aminobisphosphonate pamidronate controls influenza pathogenesis by expanding a {gamma}{delta} T cell population in humanized mice http://www.medworm.com/index.php?rid=4996711&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2F1511%3Frss%3D1 There are few antiviral drugs for treating influenza, and the emergence of antiviral resistance has further limited the available therapeutic options. Furthermore, antivirals are not invariably effective in severe influenza, such as that caused by H5N1 viruses. Thus, there is an urgent need to develop alternative therapeutic strategies. Here, we show that human V9V2 T cells expanded by the aminobisphosphonate pamidronate (PAM) kill influenza virus–infected cells and inhibit viral replication in vitro. In Rag2–/–c–/– immunodeficient mice reconstituted with human peripheral mononuclear cells (huPBMCs), PAM reduces disease severity and mortality caused by human seasonal H1N1 and avian H5N1 influenza virus, and controls the lung inflammation and viral replication.... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996711 Sun, 03 Jul 2011 23:00:00 +0100 4996711 Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope http://www.medworm.com/index.php?rid=4996710&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2F1501%3Frss%3D1 Type 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic β cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-Ag7 molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3+ regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease. (Source: The Journal of Expe... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996710 Sun, 03 Jul 2011 23:00:00 +0100 4996710 Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth http://www.medworm.com/index.php?rid=4996709&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2F1485%3Frss%3D1 Regulatory T cells (T reg cells) are characterized by the expression of the forkhead lineage-specific transcription factor Foxp3, and their main function is to suppress T cells. While evaluating T reg cells, we identified a population of Foxp3-positive cells that were CD11b+F4/80+CD68+, indicating macrophage origin. These cells were observed in spleen, lymph nodes, bone marrow, thymus, liver, and other tissues of naive animals. To characterize this subpopulation of macrophages, we devised a strategy to purify CD11b+F4/80+Foxp3+ macrophages using Foxp3-GFP mice. Analysis of CD11b+F4/80+Foxp3+ macrophage function indicated that these cells inhibited the proliferation of T cells, whereas Foxp3– macrophages did not. Suppression of T cell proliferation was mediated through soluble factors... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996709 Sun, 03 Jul 2011 23:00:00 +0100 4996709 FoxM1 mediates the progenitor function of type II epithelial cells in repairing alveolar injury induced by Pseudomonas aeruginosa http://www.medworm.com/index.php?rid=4996708&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2F1473%3Frss%3D1 In this study, we observed that pneumonia induced by intratracheal instillation of Pseudomonas aeruginosa (PA) in mice increased the expression of the forkhead transcription factor FoxM1 in type II cells coincidentally with the induction of alveolar epithelial barrier repair. FoxM1 was preferentially expressed in the Sca-1+ subpopulation of progenitor type II cells. In mice lacking FoxM1 specifically in type II cells, type II cells showed decreased proliferation and impaired trans-differentiation into type I cells. Lungs of these mice also displayed defective alveolar barrier repair after injury. Expression of FoxM1 in the knockout mouse lungs partially rescued the defective trans-differentiation phenotype. Thus, expression of FoxM1 in type II cells is essential for their proliferation and... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996708 Sun, 03 Jul 2011 23:00:00 +0100 4996708 Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44 http://www.medworm.com/index.php?rid=4996707&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F208%2F7%2F1459%3Frss%3D1 Tissue fibrosis is a major cause of morbidity, and idiopathic pulmonary fibrosis (IPF) is a terminal illness characterized by unremitting matrix deposition in the lung. The mechanisms that control progressive fibrosis are unknown. Myofibroblasts accumulate at sites of tissue remodeling and produce extracellular matrix components such as collagen and hyaluronan (HA) that ultimately compromise organ function. We found that targeted overexpression of HAS2 (HA synthase 2) by myofibroblasts produced an aggressive phenotype leading to severe lung fibrosis and death after bleomycin-induced injury. Fibroblasts isolated from transgenic mice overexpressing HAS2 showed a greater capacity to invade matrix. Conditional deletion of HAS2 in mesenchymal cells abrogated the invasive fibroblast phenotype, i... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=4996707 Sun, 03 Jul 2011 23:00:00 +0100 4996707