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. Sat, 20 Mar 2010 15:43:25 +0100 http://www.medworm.com/index.php?rid=3369275&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F671%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369275 Mon, 15 Mar 2010 17:12:57 +0100 3369275 http://www.medworm.com/index.php?rid=3369274&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F669%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369274 Mon, 15 Mar 2010 17:12:57 +0100 3369274 http://www.medworm.com/index.php?rid=3369273&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F651%3Frss%3D1 In vitro differentiated CD8+ T cells have been the primary focus of immunotherapy of cancer with little focus on CD4+ T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4+ T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8+, B, natural killer (NK), and NKT cells. Proper ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369273 Mon, 15 Mar 2010 17:12:57 +0100 3369273 http://www.medworm.com/index.php?rid=3369272&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F637%3Frss%3D1 Adoptive transfer of large numbers of tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8+ CTLs, with much less emphasis on the role and contribution of CD4+ T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4+ T cells developed cytotoxic activity, and tumor rejection was dependent on class II–restricted rec... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369272 Mon, 15 Mar 2010 17:12:57 +0100 3369272 http://www.medworm.com/index.php?rid=3369271&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F623%3Frss%3D1 This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369271 Mon, 15 Mar 2010 17:12:57 +0100 3369271 http://www.medworm.com/index.php?rid=3369270&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F607%3Frss%3D1 B cell receptors (BCRs) generate tonic signals critical for B cell survival and early B cell development. To determine whether these signals also mediate the development of transitional and mature B cells, we examined B cell development using a mouse strain in which nonautoreactive immunoglobulin heavy and light chain–targeted B cells express low surface BCR levels. We found that reduced BCR expression translated into diminished tonic BCR signals that strongly impaired the development of transitional and mature B cells. Constitutive expression of Bcl-2 did not rescue the differentiation of BCR-low B cells, suggesting that this defect was not related to decreased cell survival. In contrast, activation of the Ras pathway rescued the differentiation of BCR-low immature B cells both in v... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369270 Mon, 15 Mar 2010 17:12:57 +0100 3369270 http://www.medworm.com/index.php?rid=3369269&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F591%3Frss%3D1 RNA splicing is an increasingly recognized regulator of immunity. Here, we demonstrate that after Mycobacterium tuberculosis infection (mRNA) il12rb1 is spliced by dendritic cells (DCs) to form an alternative (mRNA) il12rb1tm that encodes the protein IL-12Rβ1TM. Compared with IL-12Rβ1, IL-12Rβ1TM contains an altered C-terminal sequence and lacks a transmembrane domain. Expression of IL-12Rβ1TM occurs in CD11c+ cells in the lungs during M. tuberculosis infection. Selective reconstitution of il12rb1–/– DCs with (mRNA) il12rb1 and/or (mRNA) il12rb1tm demonstrates that IL-12Rβ1TM augments IL-12Rβ1-dependent DC migration and activation of M. tuberculosis-specific T cells. It cannot mediate these activities independently of IL12Rβ1. We hypothesize t... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369269 Mon, 15 Mar 2010 17:12:57 +0100 3369269 http://www.medworm.com/index.php?rid=3369268&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F579%3Frss%3D1 DNAX adaptor protein 12 (DAP12) is a trans-membrane adaptor molecule that transduces activating signals in NK and myeloid cells. Absence of functional Dap12 results in osteoclast defects and bone abnormalities. Because DAP12 has no extracelluar binding domains, it must pair with cell surface receptors for signal transduction. There are at least 15 known DAP12-associating cell surface receptors with distinct temporal and cell type–specific expression patterns. Our aim was to determine which receptors may be important in DAP12-associated bone pathologies. Here, we identify myeloid DAP12-associating lectin (MDL)-1 receptor (also known as CLEC5A) as a key regulator of synovial injury and bone erosion during autoimmune joint inflammation. Activation of MDL-1 leads to enhanced recruitment ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369268 Mon, 15 Mar 2010 17:12:57 +0100 3369268 http://www.medworm.com/index.php?rid=3369267&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F565%3Frss%3D1 Interleukin (IL)-10 produced by regulatory T cell subsets is important for the prevention of autoimmunity and immunopathology, but little is known about the phenotype and function of IL-10–producing memory T cells. Human CD4+CCR6+ memory T cells contained comparable numbers of IL-17– and IL-10–producing cells, and CCR6 was induced under both Th17-promoting conditions and upon tolerogenic T cell priming with transforming growth factor (TGF)–β. In normal human spleens, the majority of CCR6+ memory T cells were in the close vicinity of CCR6+ myeloid dendritic cells (mDCs), and strikingly, some of them were secreting IL-10 in situ. Furthermore, CCR6+ memory T cells produced suppressive IL-10 but not IL-2 upon stimulation with autologous immature mDCs ex vivo, and s... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369267 Mon, 15 Mar 2010 17:12:57 +0100 3369267 http://www.medworm.com/index.php?rid=3369266&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F553%3Frss%3D1 Migration to intestinal mucosa putatively depends on local activation because gastrointestinal lymphoid tissue induces expression of intestinal homing molecules, whereas skin-draining lymph nodes do not. This paradigm is difficult to reconcile with reports of intestinal T cell responses after alternative routes of immunization. We reconcile this discrepancy by demonstrating that activation within spleen results in intermediate induction of homing potential to the intestinal mucosa. We further demonstrate that memory T cells within small intestine epithelium do not routinely recirculate with memory T cells in other tissues, and we provide evidence that homing is similarly dynamic in humans after subcutaneous live yellow fever vaccine immunization. These data explain why systemic immunizatio... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369266 Mon, 15 Mar 2010 17:12:57 +0100 3369266 http://www.medworm.com/index.php?rid=3369257&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2Fi5%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369257 Mon, 15 Mar 2010 17:12:57 +0100 3369257 http://www.medworm.com/index.php?rid=3369265&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F535%3Frss%3D1 Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4+ and + T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a–/– mice confirmed an essential role for IL-17A. Mechanistically, using ifn–/–, il10–/–, il10–/–il12p40–/–, and il10–/–il17a–/– mice and TGF-β blockade, we demonstrate that IL-17A–driven fibrosis is supp... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369265 Mon, 15 Mar 2010 17:12:56 +0100 3369265 http://www.medworm.com/index.php?rid=3369264&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F521%3Frss%3D1 This study demonstrates a key, novel requirement for DC trans-presented IL-15 in promoting effector CD8 T cell survival in the respiratory tract after virus infection, and suggests that this trans-presentation could be an important target for the development of unique antiviral therapies and more effective vaccine strategies. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369264 Mon, 15 Mar 2010 17:12:56 +0100 3369264 http://www.medworm.com/index.php?rid=3369263&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F505%3Frss%3D1 We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4+ T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3+ ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4+ T lymphocytes through the activation of the interleukin-6–STAT3 pathway, inh... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369263 Mon, 15 Mar 2010 17:12:56 +0100 3369263 http://www.medworm.com/index.php?rid=3369262&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F491%3Frss%3D1 This study may be useful in paving the way toward a more rational development of second generation antiangiogenic combination therapies and in providing, for the first time, a murine model to study this. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369262 Mon, 15 Mar 2010 17:12:56 +0100 3369262 http://www.medworm.com/index.php?rid=3369261&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F475%3Frss%3D1 The function of microRNAs (miRNAs) in hematopoietic stem cells (HSCs), committed progenitors, and leukemia stem cells (LSCs) is poorly understood. We show that miR-29a is highly expressed in HSC and down-regulated in hematopoietic progenitors. Ectopic expression of miR-29a in mouse HSC/progenitors results in acquisition of self-renewal capacity by myeloid progenitors, biased myeloid differentiation, and the development of a myeloproliferative disorder that progresses to acute myeloid leukemia (AML). miR-29a promotes progenitor proliferation by expediting G1 to S/G2 cell cycle transitions. miR-29a is overexpressed in human AML and, like human LSC, miR-29a-expressing myeloid progenitors serially transplant AML. Our data indicate that miR-29a regulates early hematopoiesis and suggest that miR... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369261 Mon, 15 Mar 2010 17:12:56 +0100 3369261 http://www.medworm.com/index.php?rid=3369260&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F465%3Frss%3D1 Systemic exacerbation of allergic responses, in which mast cells play a critical role, results in life-threatening anaphylactic shock. Sphingosine-1–phosphate (S1P), a ligand for a family of G protein–coupled receptors, is a new addition to the repertoire of bioactive lipids secreted by activated mast cells. Yet little is known of its role in human mast cell functions and in anaphylaxis. We show that S1P2 receptors play a critical role in regulating human mast cell functions, including degranulation and cytokine and chemokine release. Immunoglobulin E–triggered anaphylactic responses, including elevation of circulating histamine and associated pulmonary edema in mice, were significantly attenuated by the S1P2 antagonist JTE-013 and in S1P2-deficient mice, in contrast to a... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369260 Mon, 15 Mar 2010 17:12:56 +0100 3369260 http://www.medworm.com/index.php?rid=3369259&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F455%3Frss%3D1 Mast cell production of interleukin-10 (IL-10) can limit the skin pathology induced by chronic low-dose ultraviolet (UV)-B irradiation. Although the mechanism that promotes mast cell IL-10 production in this setting is unknown, exposure of the skin to UVB irradiation induces increased production of the immune modifying agent 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). We now show that 1,25(OH)2D3 can up-regulate IL-10 mRNA expression and induce IL-10 secretion in mouse mast cells in vitro. To investigate the roles of 1,25(OH)2D3 and mast cell vitamin D receptor (VDR) expression in chronically UVB-irradiated skin in vivo, we engrafted the skin of genetically mast cell–deficient WBB6F1-KitW/W-v mice with bone marrow–derived cultured mast cells derived from C57BL/6 wild-type or VDR&nd... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369259 Mon, 15 Mar 2010 17:12:56 +0100 3369259 http://www.medworm.com/index.php?rid=3369258&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F3%2F451%3Frss%3D1 The phrase "think globally, act locally" was coined in the early 1970s and directed individuals to clean up their local environment with the ultimate goal of improving the health of the entire planet. Several recent studies indicate that similar considerations apply to the immune system, in which small numbers of leukocytes, such as pulmonary dendritic cells, can modify the local immune environment in the lung and promote a positive outcome for the organism. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3369258 Mon, 15 Mar 2010 17:12:56 +0100 3369258 http://www.medworm.com/index.php?rid=3275026&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F447%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275026 Mon, 15 Feb 2010 16:21:58 +0100 3275026 http://www.medworm.com/index.php?rid=3275025&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F445%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275025 Mon, 15 Feb 2010 16:21:58 +0100 3275025 http://www.medworm.com/index.php?rid=3275024&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F443%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275024 Mon, 15 Feb 2010 16:21:58 +0100 3275024 http://www.medworm.com/index.php?rid=3275023&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F429%3Frss%3D1 This study defines an essential role for type I IFN, produced via cooperation between multiple host sensors and acting directly on nonhematopoietic cells, in the control of CHIKV. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275023 Mon, 15 Feb 2010 16:21:58 +0100 3275023 http://www.medworm.com/index.php?rid=3275022&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F417%3Frss%3D1 The classical nonhomologous end-joining (C-NHEJ) DNA double-strand break (DSB) repair pathway employs the Ku70/80 complex (Ku) for DSB recognition and the XRCC4/DNA ligase 4 (Lig4) complex for ligation. During IgH class switch recombination (CSR) in B lymphocytes, switch (S) region DSBs are joined by C-NHEJ to form junctions either with short microhomologies (MHs; "MH-mediated" joins) or no homologies ("direct" joins). In the absence of XRCC4 or Lig4, substantial CSR occurs via "alternative" end-joining (A-EJ) that generates largely MH-mediated joins. Because upstream C-NHEJ components remain in XRCC4- or Lig4-deficient B cells, residual CSR might be catalyzed by C-NHEJ using a different ligase. To address this, we have assayed for CSR in B cells deficient for Ku70, Ku80, or both Ku70 and ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275022 Mon, 15 Feb 2010 16:21:57 +0100 3275022 http://www.medworm.com/index.php?rid=3275021&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F405%3Frss%3D1 The process of somatic hypermutation (SHM) of immunoglobulin (Ig) genes requires activation-induced cytidine deaminase (AID). Although mistargeting of AID is detrimental to genome integrity, the mechanism and the cis-elements responsible for targeting of AID are largely unknown. We show that three CAGGTG cis-elements in the context of Ig enhancers are sufficient to target SHM to a nearby transcribed gene. The CAGGTG motif binds E47 in nuclear extracts of the mutating cells. Replacing CAGGTG with AAGGTG in the construct without any other E47 binding site eliminates SHM. The CA versus AA effect requires AID. CAGGTG does not enhance transcription, chromatin acetylation, or overall target gene activity. The other cis-elements of Ig enhancers alone cannot attract the SHM machinery. Collectively... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275021 Mon, 15 Feb 2010 16:21:57 +0100 3275021 http://www.medworm.com/index.php?rid=3275020&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F391%3Frss%3D1 We report that deficiency in hematopoietic CD40 reduces atherosclerosis and induces features of plaque stability. To elucidate the role of CD40–tumor necrosis factor receptor-associated factor (TRAF) signaling in atherosclerosis, we examined disease progression in mice deficient in CD40 and its associated signaling intermediates. Absence of CD40-TRAF6 but not CD40-TRAF2/3/5 signaling abolishes atherosclerosis and confers plaque fibrosis in Apoe–/– mice. Mice with defective CD40-TRAF6 signaling display a reduced blood count of Ly6Chigh monocytes, an impaired recruitment of Ly6C+ monocytes to the arterial wall, and polarization of macrophages toward an antiinflammatory regulatory M2 signature. These data unveil a role for CD40–TRAF6, but not CD40–TRAF2/3/5, inte... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275020 Mon, 15 Feb 2010 16:21:57 +0100 3275020 http://www.medworm.com/index.php?rid=3275019&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F379%3Frss%3D1 Defects in the DNA repair mechanism nucleotide excision repair (NER) may lead to tumors in xeroderma pigmentosum (XP) or to premature aging with loss of subcutaneous fat in Cockayne syndrome (CS). Mutations of mitochondrial (mt)DNA play a role in aging, but a link between the NER-associated CS proteins and base excision repair (BER)-associated proteins in mitochondrial aging remains enigmatic. We show functional increase of CSA and CSB inside mt and complex formation with mtDNA, mt human 8-oxoguanine glycosylase (mtOGG)-1, and mt single-stranded DNA binding protein (mtSSBP)-1 upon oxidative stress. MtDNA mutations are highly increased in cells from CS patients and in subcutaneous fat of aged Csbm/m and Csa–/– mice. Thus, the NER-proteins CSA and CSB localize to mt and directly ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275019 Mon, 15 Feb 2010 16:21:57 +0100 3275019 http://www.medworm.com/index.php?rid=3275018&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F365%3Frss%3D1 Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275018 Mon, 15 Feb 2010 16:21:57 +0100 3275018 http://www.medworm.com/index.php?rid=3275016&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F353%3Frss%3D1 During T cell–dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell–intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell–autonomous effe... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275016 Mon, 15 Feb 2010 16:21:57 +0100 3275016 http://www.medworm.com/index.php?rid=3275015&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F345%3Frss%3D1 Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275015 Mon, 15 Feb 2010 16:21:57 +0100 3275015 http://www.medworm.com/index.php?rid=3275014&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F339%3Frss%3D1 Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275014 Mon, 15 Feb 2010 16:21:57 +0100 3275014 http://www.medworm.com/index.php?rid=3275013&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F327%3Frss%3D1 Production of type I interferon (IFN; IFN-β) increases host susceptibility to Listeria monocytogenes, whereas type II IFN (IFN-) activates macrophages to resist infection. We show that these opposing immunological effects of IFN-β and IFN- occur because of cross talk between the respective signaling pathways. We found that cultured macrophages infected with L. monocytogenes were refractory to IFN- treatment as a result of down-regulation of the IFN- receptor (IFNGR). The soluble factor responsible for these effects was identified as host IFN-β. Accordingly, macrophages and dendritic cells (DCs) showed reduced IFNGR1 expression and reduced responsiveness to IFN- during systemic infection of IFN-β–responsive mice. Furthermore, the increased resistance of mice lackin... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275013 Mon, 15 Feb 2010 16:21:57 +0100 3275013 http://www.medworm.com/index.php?rid=3275012&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F319%3Frss%3D1 Type I interferon (IFN) /β is critical for host defense. During endotoxicosis or highly lethal bacterial infections where systemic inflammation predominates, mice deficient in IFN-/β receptor (IFNAR) display decreased systemic inflammation and improved outcome. However, human sepsis mortality often occurs during a prolonged period of immunosuppression and not from exaggerated inflammation. We used a low lethality cecal ligation and puncture (CLP) model of sepsis to determine the role of type I IFNs in host defense during sepsis. Despite increased endotoxin resistance, IFNAR–/– and chimeric mice lacking IFNAR in hematopoietic cells display increased mortality to CLP. This was not associated with an altered early systemic inflammatory response, except for decreased CXCL... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275012 Mon, 15 Feb 2010 16:21:57 +0100 3275012 http://www.medworm.com/index.php?rid=3275011&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F309%3Frss%3D1 Phospholipase C1 (PLC1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLC1 in T cell biology, we generated and examined mice with T cell–specific deletion of PLC1. We demonstrate that PLC1 deficiency affects positive and negative selection, significantly reduces single-positive thymocytes and peripheral T cells, and impairs TCR-induced proliferation and cytokine production, and the activation of ERK, JNK, AP-1, NFAT, and NF-B. Importantly, PLC1 deficiency impairs the development and function of FoxP3+ regulatory T cells, causing inflammatory/autoimmune symptoms. Therefore, PLC1 is essential for T cell development, activation, and tolerance. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275011 Mon, 15 Feb 2010 16:21:57 +0100 3275011 http://www.medworm.com/index.php?rid=3275010&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F299%3Frss%3D1 We report severely reduced IL-17F and IL-22 responses to both Candida albicans antigens and polyclonal stimulation in APECED patients with CMC. Surprisingly, these reductions are strongly associated with neutralizing autoantibodies to IL-17F and IL-22, whereas responses were normal and autoantibodies infrequent in APECED patients without CMC. Our multicenter survey revealed neutralizing autoantibodies against IL-17A (41%), IL-17F (75%), and/ or IL-22 (91%) in >150 APECED patients, especially those with CMC. We independently found autoantibodies against these Th17-produced cytokines in rare thymoma patients with CMC. The autoantibodies preceded the CMC in all informative cases. We conclude that IL-22 and IL-17F are key natural defenders against CMC and that the immunodeficiency underlyin... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275010 Mon, 15 Feb 2010 16:21:57 +0100 3275010 http://www.medworm.com/index.php?rid=3275009&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F291%3Frss%3D1 Most patients with autoimmune polyendocrine syndrome type I (APS-I) display chronic mucocutaneous candidiasis (CMC). We hypothesized that this CMC might result from autoimmunity to interleukin (IL)-17 cytokines. We found high titers of autoantibodies (auto-Abs) against IL-17A, IL-17F, and/or IL-22 in the sera of all 33 patients tested, as detected by multiplex particle-based flow cytometry. The auto-Abs against IL-17A, IL-17F, and IL-22 were specific in the five patients tested, as shown by Western blotting. The auto-Abs against IL-17A were neutralizing in the only patient tested, as shown by bioassays of IL-17A activity. None of the 37 healthy controls and none of the 103 patients with other autoimmune disorders tested had such auto-Abs. None of the patients with APS-I had auto-Abs agains... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275009 Mon, 15 Feb 2010 16:21:57 +0100 3275009 http://www.medworm.com/index.php?rid=3275008&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F281%3Frss%3D1 Lymphoid tissue inducer (LTi) cells are required for lymph node formation during fetal development, and recent evidence implies a role in mucosal immunity in the adult. LTi cells share some phenotypic features of conventional natural killer (NK; cNK) cells; however, little is known to date about the relationship between these two cell types. We show that lineage– (Lin–) CD127+RORC+ LTi-like cells in human tonsil are precursors to CD56+CD127+RORC+NKp46+ cells, which together comprise a stable RORC+ lineage. We find that LTi-like cells and their CD56+ progeny can be expanded and cloned ex vivo without loss of function and without conversion into cNK cells. Clonal analysis reveals heterogeneity of cytokine production within the CD127+ LTi-like population. Furthermore, we identify ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275008 Mon, 15 Feb 2010 16:21:57 +0100 3275008 http://www.medworm.com/index.php?rid=3275007&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F273%3Frss%3D1 The natural cytotoxicity receptor NKp46 (encoded by Ncr1) was recently shown to identify a subset of noncytotoxic, Rag-independent gut lymphocytes that express the transcription factor Rorc, produce interleukin (IL)-22, and provide innate immune protection at the intestinal mucosa. Intestinal CD3–NKp46+ cells are phenotypically heterogeneous, comprising a minority subset that resembles classical mature splenic natural killer (NK) cells (NK1.1+, Ly49+) but also a large CD127+NK1.1– subset of lymphoid tissue inducer (LTi)–like Rorc+ cells that has been proposed to include NK cell precursors. We investigated the developmental relationships between these intestinal CD3–NKp46+ subsets. Gut CD3–NKp46+ cells were related to LTi and NK cells in requiring the transcrip... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275007 Mon, 15 Feb 2010 16:21:56 +0100 3275007 http://www.medworm.com/index.php?rid=3275006&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F269%3Frss%3D1 A population of cells that expresses the NK cell receptor NKp46 and produces interleukin (IL)-22 have recently attracted considerable attention. The identity of these cells is still the subject of speculation, being variably defined as a novel NK cell subset or as a population containing conventional NK (cNK) cell precursors. In this issue, two studies shed light on this conundrum, demonstrating that NKp46+ IL-22+ cells and cNK cells belong to distinct lineages. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275006 Mon, 15 Feb 2010 16:21:56 +0100 3275006 http://www.medworm.com/index.php?rid=3275005&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F266%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275005 Mon, 15 Feb 2010 16:21:56 +0100 3275005 http://www.medworm.com/index.php?rid=3275004&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F265-a%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275004 Mon, 15 Feb 2010 16:21:56 +0100 3275004 http://www.medworm.com/index.php?rid=3275003&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F265%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275003 Mon, 15 Feb 2010 16:21:56 +0100 3275003 http://www.medworm.com/index.php?rid=3275002&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F264-b%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275002 Mon, 15 Feb 2010 16:21:56 +0100 3275002 http://www.medworm.com/index.php?rid=3275001&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F264-a%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275001 Mon, 15 Feb 2010 16:21:56 +0100 3275001 http://www.medworm.com/index.php?rid=3275000&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F2%2F264%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3275000 Mon, 15 Feb 2010 16:21:56 +0100 3275000 http://www.medworm.com/index.php?rid=3184549&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2Fi4%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184549 Mon, 18 Jan 2010 17:03:37 +0100 3184549 http://www.medworm.com/index.php?rid=3184547&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2Fi3%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184547 Mon, 18 Jan 2010 17:03:37 +0100 3184547 http://www.medworm.com/index.php?rid=3184568&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F247%3Frss%3D1 T cell development requires phosphatidylinositol 3-kinase (PI3K) signaling with contributions from both the class IA, p110, and class IB, p110 catalytic subunits. However, the receptors on immature T cells by which each of these PI3Ks are activated have not been identified, nor has the mechanism behind their functional redundancy in the thymus. Here, we show that PI3K signaling from the preTCR requires p110, but not p110. Mice deficient for the class IB regulatory subunit p101 demonstrated the requirement for p101 in T cell development, implicating G protein–coupled receptor signaling in β-selection. We found evidence of a role for CXCR4 using small molecule antagonists in an in vitro model of β-selection and demonstrated a requirement for CXCR4 during thymic development in... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184568 Mon, 18 Jan 2010 17:03:36 +0100 3184568 http://www.medworm.com/index.php?rid=3184567&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F237%3Frss%3D1 Human thymocytes, unlike mouse thymocytes, express major histocompatibility complex (MHC) class II molecules on their surface, especially during the fetal and perinatal stages. Based on this observation, we previously identified a novel developmental pathway for the generation of CD4+ T cells via interactions between MHC class II–expressing thymocytes (thymocyte–thymocyte [T–T] interactions) with a transgenic mouse system. However, the developmental dissection of this T–T interaction in humans has not been possible because of the lack of known cellular molecules specific for T–T CD4+ T cells. We show that promyelocytic leukemia zinc finger protein (PLZF) is a useful marker for the identification of T–T CD4+ T cells. With this analysis, we determined that... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184567 Mon, 18 Jan 2010 17:03:36 +0100 3184567 http://www.medworm.com/index.php?rid=3184566&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F223%3Frss%3D1 We describe a quantitative model for assessing the cytolytic activity of antigen-specific CD8+ T cells in vitro and in vivo in which the concentration of antigen-specific CD8+ T cells determines the efficiency with which these cells kill cognate antigen–expressing melanoma cells in packed cell pellets, in three-dimensional collagen-fibrin gels in vitro, and in established melanomas in vivo. In combination with a clonogenic assay for melanoma cells, collagen-fibrin gels are 4,500–5,500-fold more sensitive than the packed cell pellet–type assays generally used to measure CD8+ T cell cytolytic activity. An equation previously used to describe neutrophil bactericidal activity in vitro and in vivo also describes antigen-specific CD8+ T cell–mediated cytolysis of cognate ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184566 Mon, 18 Jan 2010 17:03:36 +0100 3184566 http://www.medworm.com/index.php?rid=3184565&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F207%3Frss%3D1 The nonclassical major histocompatibility complex (MHC) Qa-1b accommodates monomorphic leader peptides and functions as a ligand for germ line receptors CD94/NKG2, which are expressed by natural killer cells and CD8+ T cells. We here describe that the conserved peptides are replaced by a novel peptide repertoire of surprising diversity as a result of impairments in the antigen-processing pathway. This novel peptide repertoire represents immunogenic neoantigens for CD8+ T cells, as we found that these Qa-1b–restricted T cells dominantly participated in the response to tumors with processing deficiencies. A surprisingly wide spectrum of target cells, irrespective of transformation status, MHC background, or type of processing deficiency, was recognized by this T cell subset, complying ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184565 Mon, 18 Jan 2010 17:03:36 +0100 3184565 http://www.medworm.com/index.php?rid=3184564&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F189%3Frss%3D1 Recent studies have challenged the view that Langerhans cells (LCs) constitute the exclusive antigen-presenting cells of the skin and suggest that the dermal dendritic cell (DDC) network is exceedingly complex. Using knockin mice to track and ablate DCs expressing langerin (CD207), we discovered that the dermis contains five distinct DC subsets and identified their migratory counterparts in draining lymph nodes. Based on this refined classification, we demonstrated that the quantitatively minor CD207+ CD103+ DDC subset is endowed with the unique capability of cross-presenting antigens expressed by keratinocytes irrespective of the presence of LCs. We further showed that Y-Ae, an antibody that is widely used to monitor the formation of complexes involving I-Ab molecules and a peptide derive... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184564 Mon, 18 Jan 2010 17:03:36 +0100 3184564 http://www.medworm.com/index.php?rid=3184563&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F173%3Frss%3D1 We present evidence that TI-2 antigens decorated with ligands of inhibitory sialic acid–binding Ig-like lectins (siglecs) are poorly immunogenic and can induce tolerance to subsequent challenge with immunogenic antigen. Two siglecs, CD22 and Siglec-G, contributed to tolerance induction, preventing plasma cell differentiation or survival. Although mutations in CD22 and its signaling machinery have been associated with dysregulated B cell development and autoantibody production, previous analyses failed to identify a tolerance defect in antigen-specific mutant B cells. Our results support a role for siglecs in B cell self-/nonself-discrimination, namely suppressing responses to self-associated antigens while permitting rapid "missing self"–responses to unsialylated multimeric ant... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184563 Mon, 18 Jan 2010 17:03:36 +0100 3184563 http://www.medworm.com/index.php?rid=3184562&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F155%3Frss%3D1 Engagement of cytokine receptors by specific ligands activate Janus kinase–signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC gen... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184562 Mon, 18 Jan 2010 17:03:36 +0100 3184562 http://www.medworm.com/index.php?rid=3184561&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F141%3Frss%3D1 High-affinity antibodies are generated by somatic hypermutation with nucleotide substitutions introduced into the IgV in a semirandom fashion, but with intrinsic mutational hotspots strategically located to optimize antibody affinity maturation. The process is dependent on activation-induced deaminase (AID), an enzyme that can deaminate deoxycytidine in DNA in vitro, where its activity is sensitive to the identity of the 5'-flanking nucleotide. As a critical test of whether such DNA deamination activity underpins antibody diversification and to gain insight into the extent to which the antibody mutation spectrum is dependent on the intrinsic substrate specificity of AID, we investigated whether it is possible to change the IgV mutation spectrum by altering AID’s active site such that... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184561 Mon, 18 Jan 2010 17:03:36 +0100 3184561 http://www.medworm.com/index.php?rid=3184560&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F129%3Frss%3D1 Neutrophils kill microbes with reactive oxygen species generated by the NADPH oxidase, an enzyme which moves electrons across membranes. Voltage-gated proton channels (voltage-sensing domain only protein [VSOP]/Hv1) are required for high-level superoxide production by phagocytes, but the mechanism of this effect is not established. We show that neutrophils from VSOP/Hv1–/– mice lack proton currents but have normal electron currents, indicating that these cells have a fully functional oxidase that cannot conduct protons. VSOP/Hv1–/– neutrophils had a more acidic cytosol, were more depolarized, and produced less superoxide and hydrogen peroxide than neutrophils from wild-type mice. Hydrogen peroxide production was rescued by providing an artificial conductance with gr... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184560 Mon, 18 Jan 2010 17:03:36 +0100 3184560 http://www.medworm.com/index.php?rid=3184559&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F117%3Frss%3D1 Progranulin (PGRN) is a widely expressed protein involved in diverse biological processes. Haploinsufficiency of PGRN in the human causes tau-negative, ubiquitin-positive frontotemporal dementia (FTD). However, the mechanisms are unknown. To explore the role of PGRN in vivo, we generated PGRN-deficient mice. Macrophages from these mice released less interleukin-10 and more inflammatory cytokines than wild type (WT) when exposed to bacterial lipopolysaccharide. PGRN-deficient mice failed to clear Listeria monocytogenes infection as quickly as WT and allowed bacteria to proliferate in the brain, with correspondingly greater inflammation than in WT. PGRN-deficient macrophages and microglia were cytotoxic to hippocampal cells in vitro, and PGRN-deficient hippocampal slices were hypersusceptibl... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184559 Mon, 18 Jan 2010 17:03:36 +0100 3184559 http://www.medworm.com/index.php?rid=3184558&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F101%3Frss%3D1 We report that corneal HSV-1 infection drives lymphangiogenesis and that corneal lymphatics persist past the resolution of infection. The mechanism of HSV-1–induced lymphangiogenesis was distinct from the described mechanisms of inflammatory lymphangiogenesis. HSV-1–elicited lymphangiogenesis was strictly dependent on VEGF-A/VEGFR-2 signaling but not on VEGFR-3 ligands. Macrophages played no role in the induction of lymphangiogenesis and were not a detectable source of VEGF-A. Rather, using VEGF-A reporter transgenic mice, we have identified infected epithelial cells as the primary source of VEGF-A during HSV-1 infection. Our results indicate that HSV-1 directly induces vascularization of the cornea through up-regulation of VEGF-A expression. (Source: The Journal of Experimenta... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184558 Mon, 18 Jan 2010 17:03:36 +0100 3184558 http://www.medworm.com/index.php?rid=3184557&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F85%3Frss%3D1 Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-β and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigen... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184557 Mon, 18 Jan 2010 17:03:36 +0100 3184557 http://www.medworm.com/index.php?rid=3184556&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F77%3Frss%3D1 Vascular and neuronal networks share a similar branching morphology, and emerging evidence implicates common mechanisms in the formation of both systems. -Catenin is considered a neuronal catenin regulating neuron cell–cell adhesion and cell motility. Here, we report expression of -catenin in vascular endothelium, and show that deletion of only one allele of -catenin is sufficient to impair endothelial cell motility and vascular assembly in vitro and pathological angiogenesis in vivo, thereby inhibiting tumor growth and wound healing. In contrast, deletion of one or both allele of -catenin had no effects on hormone-induced physiological angiogenesis in the uterus. Molecular analysis confirmed a gene dosage effect of -catenin on Rho GTPase activity. Moreover, we show that inflammatory... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184556 Mon, 18 Jan 2010 17:03:36 +0100 3184556 http://www.medworm.com/index.php?rid=3184555&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F61%3Frss%3D1 CD8+ cytotoxic T lymphocyte (CTL)–mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q < 0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most fre... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184555 Mon, 18 Jan 2010 17:03:36 +0100 3184555 http://www.medworm.com/index.php?rid=3184554&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F51%3Frss%3D1 Retroviruses pack multiple genes into relatively small genomes by encoding several genes in the same genomic region with overlapping reading frames. Both sense and antisense HIV-1 transcripts contain open reading frames for known functional proteins as well as numerous alternative reading frames (ARFs). At least some ARFs have the potential to encode proteins of unknown function, and their antigenic properties can be considered as cryptic epitopes (CEs). To examine the extent of active immune response to virally encoded CEs, we analyzed human leukocyte antigen class I–associated polymorphisms in HIV-1 gag, pol, and nef genes from a large cohort of South Africans with chronic infection. In all, 391 CEs and 168 conventional epitopes were predicted, with the majority (307; 79%) of CEs d... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184554 Mon, 18 Jan 2010 17:03:36 +0100 3184554 http://www.medworm.com/index.php?rid=3184544&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2Fi2%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184544 Mon, 18 Jan 2010 17:03:36 +0100 3184544 http://www.medworm.com/index.php?rid=3184540&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2Fi1%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184540 Mon, 18 Jan 2010 17:03:36 +0100 3184540 http://www.medworm.com/index.php?rid=3184553&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F39%3Frss%3D1 We examined whether A3G-edited defective viruses, which are known to express truncated or misfolded viral proteins, activate HIV-1–specific (HS) CD8+ cytotoxic T lymphocytes (CTLs). To this end, we compared the immunogenicity of cells infected with wild-type or Vif-deleted viruses in the presence or absence of the cytidine deaminase. The inhibitory effect of A3G on HIV replication was associated with a strong activation of cocultivated HS-CTLs. CTL activation was particularly marked with Vif-deleted HIV and with viruses harboring A3G. Enzymatically inactive A3G mutants failed to enhance CTL activation. We also engineered proviruses bearing premature stop codons in their genome as scars of A3G editing. These viruses were not infectious but potently activated HS-CTLs. Therefore, the po... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184553 Mon, 18 Jan 2010 17:03:35 +0100 3184553 http://www.medworm.com/index.php?rid=3184552&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F29%3Frss%3D1 In this study, we generated a MASP-1– and MASP-3–deficient mouse model (Masp1/3–/–) and found that no activation of the alternative pathway was observed in Masp1/3–/– serum. Mass spectrometric analysis revealed that circulating complement factor D (Df) in Masp1/3–/– mice is a zymogen (pro-Df) with the activation peptide QPRGR at its N terminus. These results suggested that Masp1/3–/– mice failed to convert pro-Df to its active form, whereas it was generally accepted that the activation peptide of pro-Df is removed during its secretion and factor D constitutively exists in an active form in the circulation. Furthermore, recombinant MASP-1 converted pro-Df to the active form in vitro, although the activation mechanism of pro-Df by M... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184552 Mon, 18 Jan 2010 17:03:35 +0100 3184552 http://www.medworm.com/index.php?rid=3184551&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F17%3Frss%3D1 We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre+ Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Gi-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell–cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation. (Sou... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184551 Mon, 18 Jan 2010 17:03:35 +0100 3184551 http://www.medworm.com/index.php?rid=3184550&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F7%3Frss%3D1 This study thus identifies CLM-1 as a negative regulator of myeloid effector cells in autoimmune demyelination. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184550 Mon, 18 Jan 2010 17:03:35 +0100 3184550 http://www.medworm.com/index.php?rid=3184548&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F4%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184548 Mon, 18 Jan 2010 17:03:35 +0100 3184548 http://www.medworm.com/index.php?rid=3184546&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F3-a%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184546 Mon, 18 Jan 2010 17:03:35 +0100 3184546 http://www.medworm.com/index.php?rid=3184545&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F3%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184545 Mon, 18 Jan 2010 17:03:35 +0100 3184545 http://www.medworm.com/index.php?rid=3184543&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F2-b%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184543 Mon, 18 Jan 2010 17:03:35 +0100 3184543 http://www.medworm.com/index.php?rid=3184542&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F2-a%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184542 Mon, 18 Jan 2010 17:03:35 +0100 3184542 http://www.medworm.com/index.php?rid=3184541&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F207%2F1%2F2%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3184541 Mon, 18 Jan 2010 17:03:35 +0100 3184541 http://www.medworm.com/index.php?rid=3110365&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3159%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110365 Mon, 21 Dec 2009 17:01:05 +0100 3110365 http://www.medworm.com/index.php?rid=3110331&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2Fi35%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110331 Mon, 21 Dec 2009 17:01:05 +0100 3110331 http://www.medworm.com/index.php?rid=3110330&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2Fi34%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110330 Mon, 21 Dec 2009 17:01:05 +0100 3110330 http://www.medworm.com/index.php?rid=3110329&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2Fi33%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110329 Mon, 21 Dec 2009 17:01:05 +0100 3110329 http://www.medworm.com/index.php?rid=3110328&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2Fi32%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110328 Mon, 21 Dec 2009 17:01:05 +0100 3110328 http://www.medworm.com/index.php?rid=3110364&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3157%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110364 Mon, 21 Dec 2009 17:01:04 +0100 3110364 http://www.medworm.com/index.php?rid=3110363&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3143%3Frss%3D1 This study identifies MGL1 as a novel regulator of inflammatory monocyte trafficking to adipose tissue in response to DIO. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110363 Mon, 21 Dec 2009 17:01:04 +0100 3110363 http://www.medworm.com/index.php?rid=3110362&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3131%3Frss%3D1 MLL-AF4 fusion is a hallmark genetic abnormality in infant B-acute lymphoblastic leukemia (B-ALL) known to arise in utero. The cellular origin of leukemic fusion genes during human development is difficult to ascertain. The bone marrow (BM) microenvironment plays an important role in the pathogenesis of several hematological malignances. BM mesenchymal stem cells (BM-MSC) from 38 children diagnosed with cytogenetically different acute leukemias were screened for leukemic fusion genes. Fusion genes were absent in BM-MSCs of childhood leukemias carrying TEL-AML1, BCR-ABL, AML1-ETO, MLL-AF9, MLL-AF10, MLL-ENL or hyperdiploidy. However, MLL-AF4 was detected and expressed in BM-MSCs from all cases of MLL-AF4+ B-ALL. Unlike leukemic blasts, MLL-AF4+ BM-MSCs did not display monoclonal Ig gene rea... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110362 Mon, 21 Dec 2009 17:01:04 +0100 3110362 http://www.medworm.com/index.php?rid=3110361&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3115%3Frss%3D1 CD103+ dendritic cells (DCs) in nonlymphoid tissues are specialized in the cross-presentation of cell-associated antigens. However, little is known about the mechanisms that regulate the development of these cells. We show that two populations of CD11c+MHCII+ cells separated on the basis of CD103 and CD11b expression coexist in most nonlymphoid tissues with the exception of the lamina propria. CD103+ DCs are related to lymphoid organ CD8+ DCs in that they are derived exclusively from pre-DCs under the control of fms-like tyrosine kinase 3 (Flt3) ligand, inhibitor of DNA protein 2 (Id2), and IFN regulatory protein 8 (IRF8). In contrast, lamina propria CD103+ DCs express CD11b and develop independently of Id2 and IRF8. The other population of CD11c+MHCII+ cells in tissues, which is CD103&nda... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110361 Mon, 21 Dec 2009 17:01:04 +0100 3110361 http://www.medworm.com/index.php?rid=3110360&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3101%3Frss%3D1 We report that CD103 and CX3CR1 phenotypically and functionally characterize distinct subsets of lamina propria cells. In contrast to CD103+ DC, CX3CR1+ cells represent a nonmigratory gut-resident population with slow turnover rates and poor responses to FLT-3L and granulocyte/macrophage colony-stimulating factor. Direct visualization of cells in lymph vessels and flow cytometry of mouse intestinal lymph revealed that CD103+ DCs, but not CX3CR1-expressing cells, migrate into the gut draining mesenteric lymph nodes (LNs) under steady-state and inflammatory conditions. Moreover, CX3CR1+ cells displayed poor T cell stimulatory capacity in vitro and in vivo after direct injection of cells into intestinal lymphatics and appeared to be less efficient at generating RA compared with CD103+ DC. The... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110360 Mon, 21 Dec 2009 17:01:04 +0100 3110360 http://www.medworm.com/index.php?rid=3110359&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3089%3Frss%3D1 Most tissues develop from stem cells and precursors that undergo differentiation as their proliferative potential decreases. Mature differentiated cells rarely proliferate and are replaced at the end of their life by new cells derived from precursors. Langerhans cells (LCs) of the epidermis, although of myeloid origin, were shown to renew in tissues independently from the bone marrow, suggesting the existence of a dermal or epidermal progenitor. We investigated the mechanisms involved in LC development and homeostasis. We observed that a single wave of LC precursors was recruited in the epidermis of mice around embryonic day 18 and acquired a dendritic morphology, major histocompatibility complex II, CD11c, and langerin expression immediately after birth. Langerin+ cells then undergo a mas... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110359 Mon, 21 Dec 2009 17:01:04 +0100 3110359 http://www.medworm.com/index.php?rid=3110358&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3073%3Frss%3D1 The inflammatory response is one of several host alert mechanisms that recruit neutrophils from the circulation to the area of infection. We demonstrate that Bordetella, a bacterial pathogen, exploits an antiinflammatory cytokine, interleukin-10 (IL-10), to evade the host immune system. We identified a Bordetella effector, BopN, that is translocated into the host cell via the type III secretion system, where it induces enhanced production of IL-10. Interestingly, the BopN effector translocates itself into the nucleus and is involved in the down-regulation of mitogen-activated protein kinases. Using pharmacological blockade, we demonstrated that BopN-induced IL-10 production is mediated, at least in part, by its ability to block the extracellular signal-regulated kinase pathway. We also sho... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110358 Mon, 21 Dec 2009 17:01:04 +0100 3110358 http://www.medworm.com/index.php?rid=3110357&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3061%3Frss%3D1 We examined H. pylori colonization in mice to test the hypothesis that host phenotype selects for H. pylori (Le) phenotypes. When wild-type and Leb-expressing transgenic FVB/N mice were challenged with H. pylori strain HP1, expressing Lex and Ley, we found that bacterial populations recovered after 8 mo from Leb-transgenic, but not wild-type, mice expressed Leb. Changes in Le phenotype were linked to variation of a putative galactosyltransferase gene (β-(1,3)galT); mutagenesis and complementation revealed its essential role in type I antigen expression. These studies indicate that H. pylori evolves to resemble the host's gastric Le phenotype, and reveal a bacterial genetic locus that is subject to host-driven selection pressure. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110357 Mon, 21 Dec 2009 17:01:04 +0100 3110357 http://www.medworm.com/index.php?rid=3110356&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3047%3Frss%3D1 We report interleukin (IL)-23–mediated gelatinase A (matrixmetalloproteinase [MMP]-2) up-regulation in the ileum of infected mice. MMP-2 deficiency as well as therapeutic or prophylactic selective gelatinase blockage protected mice from the development of T. gondii–induced immunopathology. Moreover, IL-23–dependent up-regulation of IL-22 was essential for the development of ileitis, whereas IL-17 was down-regulated and dispensable. CD4+ T cells were the main source of IL-22 in the small intestinal lamina propria. Thus, IL-23 regulates small intestinal inflammation via IL-22 but independent of IL-17. Gelatinases may be useful targets for treatment of intestinal inflammation. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110356 Mon, 21 Dec 2009 17:01:04 +0100 3110356 http://www.medworm.com/index.php?rid=3110355&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3031%3Frss%3D1 Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in the rare recessive genetic disorder xeroderma pigmentosum (XP). Many XP patients are compound heterozygotes with a "causative" XPD point mutation R683W and different second mutant alleles, considered "null alleles." However, there is marked clinical heterogeneity (including presence or absence of skin cancers or neurological degeneration) in these XPD/R683W patients, thus suggesting a contribution of the second allele. Here, we report XP patients carrying XPD/R683W and a second XPD allele either XPD/Q452X, /I455del, or /199insPP. We performed a systematic study of the effect of these XPD mutations on several enzymatic functions of TFIIH and found that each mutation exhibited unique biochemical properties. A... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110355 Mon, 21 Dec 2009 17:01:04 +0100 3110355 http://www.medworm.com/index.php?rid=3110354&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3015%3Frss%3D1 Both the programmed death (PD) 1–PD-ligand (PD-L) pathway and regulatory T (T reg) cells are instrumental to the maintenance of peripheral tolerance. We demonstrate that PD-L1 has a pivotal role in regulating induced T reg (iT reg) cell development and sustaining iT reg cell function. PD-L1–/– antigen-presenting cells minimally convert naive CD4 T cells to iT reg cells, showing the essential role of PD-L1 for iT reg cell induction. PD-L1–coated beads induce iT reg cells in vitro, indicating that PD-L1 itself regulates iT reg cell development. Furthermore, PD-L1 enhances and sustains Foxp3 expression and the suppressive function of iT reg cells. The obligatory role for PD-L1 in controlling iT reg cell development and function in vivo is illustrated by a marked reduct... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110354 Mon, 21 Dec 2009 17:01:04 +0100 3110354 http://www.medworm.com/index.php?rid=3110353&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F3001%3Frss%3D1 During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-B transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel–/– mice, thymic T reg cell numbers are markedly reduced as a result of a T cell–intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-β conversion of peripheral CD4+CD25– T cells into CD4+Foxp3+ cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripher... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110353 Mon, 21 Dec 2009 17:01:04 +0100 3110353 http://www.medworm.com/index.php?rid=3110352&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2987%3Frss%3D1 Most T lymphocytes appear to arise from very rare early T lineage progenitors (ETPs) in the thymus, but the transcriptional programs that specify ETP generation are not completely known. The transcription factor GATA-3 is required for the development of T lymphocytes at multiple late differentiation steps as well as for the development of thymic natural killer cells. However, a role for GATA-3 before the double-negative (DN) 3 stage of T cell development has to date been obscured both by the developmental heterogeneity of DN1 thymocytes and the paucity of ETPs. We provide multiple lines of in vivo evidence through the analysis of T cell development in Gata3 hypomorphic mutant embryos, in irradiated mice reconstituted with Gata3 mutant hematopoietic cells, and in mice conditionally ablated ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110352 Mon, 21 Dec 2009 17:01:04 +0100 3110352 http://www.medworm.com/index.php?rid=3110351&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2977%3Frss%3D1 Nuclear factor interleukin-3 (Nfil3; also known as E4-binding protein 4) is a basic region leucine zipper transcription factor that has antiapoptotic activity in vitro under conditions of growth factor withdrawal. To study the role of Nfil3 in vivo, we generated gene-targeted Nfil3-deficient (Nfil3–/–) mice. Nfil3–/– mice were born at normal Mendelian frequency and were grossly normal and fertile. Although numbers of T cells, B cells, and natural killer (NK) T cells were normal in Nfil3–/– mice, a specific disruption in NK cell development resulted in severely reduced numbers of mature NK cells in the periphery. This defect was NK cell intrinsic in nature, leading to a failure to reject MHC class I–deficient cells in vivo and reductions in both int... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110351 Mon, 21 Dec 2009 17:01:04 +0100 3110351 http://www.medworm.com/index.php?rid=3110350&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2967%3Frss%3D1 The double-stranded RNA (dsRNA) analogue poly(I:C) is a promising adjuvant for cancer vaccines because it activates both dendritic cells (DCs) and natural killer (NK) cells, concurrently promoting adaptive and innate anticancer responses. Poly(I:C) acts through two dsRNA sensors, Toll-like receptor 3 (TLR3) and melanoma differentiation-associated protein-5 (MDA5). Here, we investigated the relative contributions of MDA5 and TLR3 to poly(I:C)-mediated NK cell activation using MDA5–/–, TLR3–/–, and MDA5–/–TLR3–/– mice. MDA5 was crucial for NK cell activation, whereas TLR3 had a minor impact most evident in the absence of MDA5. MDA5 and TLR3 activated NK cells indirectly through accessory cells and induced the distinct stimulatory cytokines inte... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110350 Mon, 21 Dec 2009 17:01:04 +0100 3110350 http://www.medworm.com/index.php?rid=3110349&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2959%3Frss%3D1 A subset of HLA-B*35 alleles, B*35-Px, are strongly associated with accelerated HIV-1 disease progression for reasons that are not understood. Interestingly, the alternative set of B*35 subtypes, B*35-PY, have no detectable impact on HIV-1 disease outcomes, even though they can present identical HIV-1 epitopes as B*35-Px molecules. Thus, the differential impact of these alleles on HIV-1 disease progression may be unrelated to interactions with HIV-1–specific CD8+ T cells. Here, we show that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory MHC class I receptor expressed on dendritic cells, than does the B*35-PY molecule B*3501, even though these two B*35 molecules differ by only one amino acid and present identical HIV-1... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110349 Mon, 21 Dec 2009 17:01:04 +0100 3110349 http://www.medworm.com/index.php?rid=3110348&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2947%3Frss%3D1 Th2 cells drive protective immunity against most parasitic helminths, but few mechanisms have been demonstrated that facilitate pathogen clearance. We show that IL-4 and IL-13 protect against intestinal lumen-dwelling worms primarily by inducing intestinal epithelial cells (IECs) to differentiate into goblet cells that secrete resistin-like molecule (RELM) β. RELM-β is essential for normal spontaneous expulsion and IL-4–induced expulsion of Nippostrongylus brasiliensis and Heligmosomoides polygyrus, which both live in the intestinal lumen, but it does not contribute to immunity against Trichinella spiralis, which lives within IEC. RELM-β is nontoxic for H. polygyrus in vitro but directly inhibits the ability of worms to feed on host tissues during infection. This decre... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110348 Mon, 21 Dec 2009 17:01:04 +0100 3110348 http://www.medworm.com/index.php?rid=3110347&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2937%3Frss%3D1 Outermost barriers are critical for terrestrial animals to avoid desiccation and to protect their bodies from foreign insults. Mammalian skin consists of two sets of barriers: stratum corneum (SC) and tight junctions (TJs). How acquisition of external antigens (Ags) by epidermal Langerhans cells (LCs) occur despite these barriers has remained unknown. We show that activation-induced LCs elongate their dendrites to penetrate keratinocyte (KC) TJs and survey the extra-TJ environment located outside of the TJ barrier, just beneath the SC. Penetrated dendrites uptake Ags from the tip where Ags colocalize with langerin/Birbeck granules. TJs at KC–KC contacts allow penetration of LC dendrites by dynamically forming new claudin-dependent bicellular- and tricellulin-dependent tricellular TJs... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110347 Mon, 21 Dec 2009 17:01:04 +0100 3110347 http://www.medworm.com/index.php?rid=3110346&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2925%3Frss%3D1 In this study, we demonstrate that DC-entry is also independent of pericellular proteolysis, raising the question of whether lymphatic vessels offer preexisting entry routes. We find that the perilymphatic basement membrane of initial lymphatic vessels is discontinuous and therefore leaves gaps for entering cells. Using a newly developed in situ live cell imaging approach that allows us to dynamically visualize the cells and their extracellular environment, we demonstrate that DCs enter through these discontinuities, which are transiently mechanically dilated by the passaging cells. We further show that penetration of the underlying lymphatic endothelial layer occurs through flap valves lacking continuous intercellular junctions. Together, we demonstrate free cellular communication between... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110346 Mon, 21 Dec 2009 17:01:04 +0100 3110346 http://www.medworm.com/index.php?rid=3110345&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2915%3Frss%3D1 In conclusion, we show that nitrite can protect against toxicity in shock via sGC-dependent signaling, which may include hypoxic vasodilation necessary to maintain microcirculation and organ function, and cardioprotection. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110345 Mon, 21 Dec 2009 17:01:04 +0100 3110345 http://www.medworm.com/index.php?rid=3110344&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2907%3Frss%3D1 Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude that GCs are dynamic anatomical structures that can be reutilized by newly activated B cells during immune responses. (Source: The Jo... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110344 Mon, 21 Dec 2009 17:01:04 +0100 3110344 http://www.medworm.com/index.php?rid=3110343&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2897%3Frss%3D1 The present epidemic of diabetes is resulting in a worldwide increase in cardiovascular and microvascular complications including retinopathy. Current thinking has focused on local influences in the retina as being responsible for development of this diabetic complication. However, the contribution of circulating cells in maintenance, repair, and dysfunction of the vasculature is now becoming appreciated. Diabetic individuals have fewer endothelial progenitor cells (EPCs) in their circulation and these cells have diminished migratory potential, which contributes to their decreased reparative capacity. Using a rat model of type 2 diabetes, we show that the decrease in EPC release from diabetic bone marrow is caused by bone marrow neuropathy and that these changes precede the development of ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110343 Mon, 21 Dec 2009 17:01:04 +0100 3110343 http://www.medworm.com/index.php?rid=3110342&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2889%3Frss%3D1 We report that in endothelial cells, Ang II enhances the tyrosine phosphorylation of endothelial NO synthase (eNOS) in an AT1-, H2O2-, and PYK2-dependent manner. Low concentrations (1–100 µmol/liter) of H2O2 stimulated the phosphorylation of eNOS Tyr657 without affecting that of Ser1177, and attenuated basal and agonist-induced NO production. In isolated mouse aortae, 30 µmol/liter H2O2 induced phosphorylation of eNOS on Tyr657 and impaired acetylcholine-induced relaxation. Endothelial overexpression of a dominant-negative PYK2 mutant protected against H2O2-induced endothelial dysfunction. Correspondingly, carotid arteries from eNOS–/– mice overexpressing the nonphosphorylatable eNOS Y657F mutant were also protected against H2O2. In vivo, 3 wk of treatment wit... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110342 Mon, 21 Dec 2009 17:01:04 +0100 3110342 http://www.medworm.com/index.php?rid=3110341&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2879%3Frss%3D1 Tuberculosis remains a fatal disease caused by Mycobacterium tuberculosis, which contains various unique components that affect the host immune system. Trehalose-6,6'-dimycolate (TDM; also called cord factor) is a mycobacterial cell wall glycolipid that is the most studied immunostimulatory component of M. tuberculosis. Despite five decades of research on TDM, its host receptor has not been clearly identified. Here, we demonstrate that macrophage inducible C-type lectin (Mincle) is an essential receptor for TDM. Heat-killed mycobacteria activated Mincle-expressing cells, but the activity was lost upon delipidation of the bacteria; analysis of the lipid extracts identified TDM as a Mincle ligand. TDM activated macrophages to produce inflammatory cytokines and nitric oxide, which are complet... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110341 Mon, 21 Dec 2009 17:01:03 +0100 3110341 http://www.medworm.com/index.php?rid=3110340&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2869%3Frss%3D1 The pre- and postnatal environment may represent a window of opportunity for allergy and asthma prevention, and the hygiene hypothesis implies that microbial agents may play an important role in this regard. Using the cowshed-derived bacterium Acinetobacter lwoffii F78 together with a mouse model of experimental allergic airway inflammation, this study investigated the hygiene hypothesis, maternal (prenatal) microbial exposure, and the involvement of Toll-like receptor (TLR) signaling in prenatal protection from asthma. Maternal intranasal exposure to A. lwoffii F78 protected against the development of experimental asthma in the progeny. Maternally, A. lwoffii F78 exposure resulted in a transient increase in lung and serum proinflammatory cytokine production and up-regulation of lung TLR m... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110340 Mon, 21 Dec 2009 17:01:03 +0100 3110340 http://www.medworm.com/index.php?rid=3110339&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2865%3Frss%3D1 Mycobacterium tuberculosis is a leading killer worldwide, yet the adjuvancy of its cell wall has proven to be a valuable therapeutic tool for vaccination and immunotherapy. Much research effort has focused on the mycobacterial glycolipid trehalose-6,6’-dimycolate (TDM), a potent immunostimulant that is also known as cord factor. Now, the identification of the monocyte-inducible C-type lectin (Mincle) as an essential receptor for TDM provides new insight into the formation of the characteristic granulomas in tuberculosis and an avenue for rational adjuvant design. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110339 Mon, 21 Dec 2009 17:01:03 +0100 3110339 http://www.medworm.com/index.php?rid=3110338&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2861%3Frss%3D1 The progressive rise in the prevalence of allergic diseases since the 1970s is widely attributed to diminished exposure to microbial stimuli, resulting in dysregulated immune functions during early life. Most studies investigating the mechanism behind this phenomenon have focused on postnatal microbial exposure. But emerging evidence suggests that such programming may also occur in the developing fetus as a result of microbial stimulation of the pregnant mother. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110338 Mon, 21 Dec 2009 17:01:03 +0100 3110338 http://www.medworm.com/index.php?rid=3110337&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2858%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110337 Mon, 21 Dec 2009 17:01:03 +0100 3110337 http://www.medworm.com/index.php?rid=3110336&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2857-a%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110336 Mon, 21 Dec 2009 17:01:03 +0100 3110336 http://www.medworm.com/index.php?rid=3110335&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2857%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110335 Mon, 21 Dec 2009 17:01:03 +0100 3110335 http://www.medworm.com/index.php?rid=3110334&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2856-b%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110334 Mon, 21 Dec 2009 17:01:03 +0100 3110334 http://www.medworm.com/index.php?rid=3110333&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2856-a%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110333 Mon, 21 Dec 2009 17:01:03 +0100 3110333 http://www.medworm.com/index.php?rid=3110332&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F13%2F2856%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3110332 Mon, 21 Dec 2009 17:01:03 +0100 3110332 http://www.medworm.com/index.php?rid=3022009&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2853%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022009 Mon, 23 Nov 2009 23:26:37 +0100 3022009 http://www.medworm.com/index.php?rid=3022008&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2851%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022008 Mon, 23 Nov 2009 23:26:37 +0100 3022008 http://www.medworm.com/index.php?rid=3022007&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2837%3Frss%3D1 Hematopoietic stem cells (HSCs) are thought to reside in discrete niches through stable adhesion, yet previous studies have suggested that host HSCs can be replaced by transplanted donor HSCs, even in the absence of cytoreductive conditioning. To explain this apparent paradox, we calculated, through cell surface phenotyping and transplantation of unfractionated blood, that ~1–5% of the total pool of HSCs enters into the circulation each day. Bromodeoxyuridine (BrdU) feeding experiments demonstrated that HSCs in the peripheral blood incorporate BrdU at the same rate as do HSCs in the bone marrow, suggesting that egress from the bone marrow to the blood can occur without cell division and can leave behind vacant HSC niches. Consistent with this, repetitive daily transplantations of sma... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022007 Mon, 23 Nov 2009 23:26:37 +0100 3022007 http://www.medworm.com/index.php?rid=3022006&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2823%3Frss%3D1 The bloodstream is an important route of dissemination of invading pathogens. Most of the small bloodborne pathogens, like bacteria or viruses, are filtered by the spleen or liver sinusoids and presented to the immune system by dendritic cells (DCs) that probe these filters for the presence of foreign antigen (Ag). However, larger pathogens, like helminths or infectious emboli, that exceed 20 µm are mostly trapped in the vasculature of the lung. To determine if Ag trapped here can be presented to cells of the immune system, we used a model of venous embolism of large particulate Ag (in the form of ovalbumin [OVA]-coated Sepharose beads) in the lung vascular bed. We found that large Ags were presented and cross-presented to CD4 and CD8 T cells in the mediastinal lymph nodes (LNs) but ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022006 Mon, 23 Nov 2009 23:26:37 +0100 3022006 http://www.medworm.com/index.php?rid=3022005&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2809%3Frss%3D1 We report that these autoantibodies are present in the cord blood of women with preeclampsia and retain the ability to activate AT1 receptors. Using an autoantibody-induced animal model of preeclampsia, we show that AT1-AAs cross the mouse placenta, enter fetal circulation, and lead to small fetuses with organ growth retardation. AT1-AAs also induce apoptosis in the placentas of pregnant mice, human villous explants, and human trophoblast cells. Finally, autoantibody-induced IUGR and placental apoptosis are diminished by either losartan or an autoantibody-neutralizing peptide. Thus, these studies identify AT1-AA as a novel causative factor of preeclampsia-associated IUGR and offer two possible underlying mechanisms: a direct detrimental effect on fetal development by crossing the placenta ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022005 Mon, 23 Nov 2009 23:26:37 +0100 3022005 http://www.medworm.com/index.php?rid=3022004&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2795%3Frss%3D1 Leukocyte migration across endothelial cell borders (paracellular) and through endothelial cells (transcellular) appear to be distinct processes. During paracellular migration, membrane from a parajunctional reticulum of interconnected vesicles, the endothelial lateral border recycling compartment (LBRC), moves to surround the leukocyte in a kinesin-mediated, microtubule-dependent manner. We show that transcellular migration likewise requires targeted trafficking of LBRC membrane. We show that in addition to platelet/endothelial cell adhesion molecule (PECAM; CD31), CD99 and junctional adhesion molecule A (JAM-A), but apparently not vascular endothelial cell–specific cadherin (cadherin 5, CD144), are components of the LBRC. During transcellular migration, LBRC membrane invests the tr... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022004 Mon, 23 Nov 2009 23:26:37 +0100 3022004 http://www.medworm.com/index.php?rid=3022003&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2779%3Frss%3D1 Although Fc receptors (FcRs) for switched immunoglobulin (Ig) isotypes have been extensively characterized, FcR for IgM (FcµR) has defied identification. By retroviral expression and functional cloning, we have identified a complementary DNA (cDNA) encoding a bona fide FcµR in human B-lineage cDNA libraries. FcµR is defined as a transmembrane sialoglycoprotein of ~60 kD, which contains an extracellular Ig-like domain homologous to two other IgM-binding receptors (polymeric Ig receptor and Fc/µR) but exhibits an exclusive Fcµ-binding specificity. The cytoplasmic tail of FcµR contains conserved Ser and Tyr residues, but none of the Tyr residues match the immunoreceptor tyrosine-based activation, inhibitory, or switch motifs. Unlike other FcRs, the major ce... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022003 Mon, 23 Nov 2009 23:26:37 +0100 3022003 http://www.medworm.com/index.php?rid=3022002&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2761%3Frss%3D1 The inflammatory mediator thrombin proteolytically activates protease-activated receptor (PAR1) eliciting a transient, but reversible increase in vascular permeability. PAR1-induced dissociation of G subunit from heterotrimeric Gq and G12/G13 proteins is known to signal the increase in endothelial permeability. However, the role of released Gβ is unknown. We now show that impairment of Gβ function does not affect the permeability increase induced by PAR1, but prevents reannealing of adherens junctions (AJ), thereby persistently elevating endothelial permeability. We observed that in the naive endothelium Gβ1, the predominant Gβ isoform is sequestered by receptor for activated C kinase 1 (RACK1). Thrombin induced dissociation of Gβ1 from RACK1, resulting in Gβ1... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022002 Mon, 23 Nov 2009 23:26:37 +0100 3022002 http://www.medworm.com/index.php?rid=3022001&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2747%3Frss%3D1 Infection by Toxoplasma gondii down-regulates the host innate immune responses, such as proinflammatory cytokine production, in a Stat3-dependent manner. A forward genetic approach recently demonstrated that the type II strain fails to suppress immune responses because of a potential defect in a highly polymorphic parasite-derived kinase, ROP16. We generated ROP16-deficient type I parasites by reverse genetics and found a severe defect in parasite-induced Stat3 activation, culminating in enhanced production of interleukin (IL) 6 and IL-12 p40 in the infected macrophages. Furthermore, overexpression of ROP16 but not ROP18 in mammalian cells resulted in Stat3 phosphorylation and strong activation of Stat3-dependent promoters. In addition, kinase-inactive ROP16 failed to activate Stat3. Compa... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022001 Mon, 23 Nov 2009 23:26:37 +0100 3022001 http://www.medworm.com/index.php?rid=3022000&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2735%3Frss%3D1 West Nile virus (WNV) infection causes a life-threatening meningoencephalitis that becomes increasingly more prevalent over the age of 50 and is 40–50x more prevalent in people over the age of 70, compared with adults under the age of 40. In a mouse model of age-related vulnerability to WNV, we demonstrate that death correlates with increased viral titers in the brain and that this loss of virus control with age was the result of defects in the CD4 and CD8 T cell response against WNV. Specific age-related defects in T cell responses against dominant WNV epitopes were detected at the level of cytokine and lytic granule production, each of which are essential for resistance against WNV, and in the ability to generate multifunctional anti-WNV effector T cells, which are believed to be c... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3022000 Mon, 23 Nov 2009 23:26:37 +0100 3022000 http://www.medworm.com/index.php?rid=3021982&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2Fi31%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021982 Mon, 23 Nov 2009 23:26:37 +0100 3021982 http://www.medworm.com/index.php?rid=3021981&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2Fi30%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021981 Mon, 23 Nov 2009 23:26:37 +0100 3021981 http://www.medworm.com/index.php?rid=3021980&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2Fi29%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021980 Mon, 23 Nov 2009 23:26:37 +0100 3021980 http://www.medworm.com/index.php?rid=3021979&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2Fi28%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021979 Mon, 23 Nov 2009 23:26:37 +0100 3021979 http://www.medworm.com/index.php?rid=3021978&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2Fi27%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021978 Mon, 23 Nov 2009 23:26:37 +0100 3021978 http://www.medworm.com/index.php?rid=3021999&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2717%3Frss%3D1 We report that heparan sulfate is expressed in spermatozoa and plays an important role in the capture of HIV-1. Spermatozoa-attached virus is efficiently transmitted to DCs, macrophages, and T cells. Interaction of spermatozoa with DCs not only leads to the transmission of HIV-1 and the internalization of the spermatozoa but also results in the phenotypic maturation of DCs and the production of IL-10 but not IL-12p70. At low values of extracellular pH (~6.5 pH units), similar to those found in the vaginal mucosa after sexual intercourse, the binding of HIV-1 to the spermatozoa and the consequent transmission of HIV-1 to DCs were strongly enhanced. Our observations support the notion that far from being a passive carrier, spermatozoa acting in concert with DCs might affect the early course ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021999 Mon, 23 Nov 2009 23:26:36 +0100 3021999 http://www.medworm.com/index.php?rid=3021998&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2701%3Frss%3D1 In this study, we show that the transforming growth factor-β (TGF-β) induces the expression of the Runt-related transcription factors RUNX1 and RUNX3 in CD4+ T cells. This induction seems to be a prerequisite for the binding of RUNX1 and RUNX3 to three putative RUNX binding sites in the FOXP3 promoter. Inactivation of the gene encoding RUNX cofactor core-binding factor-β (CBFβ) in mice and small interfering RNA (siRNA)-mediated suppression of RUNX1 and RUNX3 in human T cells resulted in reduced expression of Foxp3. The in vivo conversion of naive CD4+ T cells into Foxp3+ iT reg cells was significantly decreased in adoptively transferred CbfbF/F CD4-cre naive T cells into Rag2–/– mice. Both RUNX1 and RUNX3 siRNA silenced human T reg cells and CbfbF/F CD4-cre ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021998 Mon, 23 Nov 2009 23:26:36 +0100 3021998 http://www.medworm.com/index.php?rid=3021997&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2685%3Frss%3D1 In this study, we demonstrate that Ets1 is required for the proper termination of CD4 expression during the differentiation of major histocompatability class 1 (MHC I)–restricted thymocytes, but not for other events associated with their positive selection, including the initiation of cytotoxic gene expression, corticomedullary migration, or thymus exit. We further show that Ets1 promotes expression of Runx3, a transcription factor important for CD8 T cell differentiation and the cessation of Cd4 gene expression. Enforced Runx3 expression in Ets1-deficient MHC I–restricted thymocytes largely rescued their impaired Cd4 silencing, indicating that Ets1 is not required for Runx3 function. Finally, we document that Ets1 binds at least two evolutionarily conserved regions within the ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021997 Mon, 23 Nov 2009 23:26:36 +0100 3021997 http://www.medworm.com/index.php?rid=3021996&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2671%3Frss%3D1 B cell activation factor of the TNF family (BAFF) activates noncanonical nuclear factor B (NF-B) heterodimers that promote B cell survival. We show that although MALT1 is largely dispensable for canonical NF-B signaling downstream of the B cell receptor, the absence of MALT1 results in impaired BAFF-induced phosphorylation of NF-B2 (p100), p100 degradation, and RelB nuclear translocation in B220+ B cells. This corresponds with impaired survival of MALT1–/– marginal zone (MZ) but not follicular B cells in response to BAFF stimulation in vitro. MALT1–/– MZ B cells also express higher amounts of TRAF3, a known negative regulator of BAFF receptor–mediated signaling, and TRAF3 was found to interact with MALT1. Furthermore, phenotypes associated with overexpression ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021996 Mon, 23 Nov 2009 23:26:36 +0100 3021996 http://www.medworm.com/index.php?rid=3021995&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2659%3Frss%3D1 The origin of IgM+CD27+ B lymphocytes with mutated IgV genes, which account for ~20% of human peripheral blood (PB) B cells, is controversially discussed. A generation in a primary diversification pathway, in T cell–independent immune responses, or in T cell–dependent germinal center (GC) reactions has been proposed. We show here that IgM+IgD+CD27+ and IgM+IgD–/lowCD27+ B cell subsets carry, like class-switched memory B cells, mutations in the Bcl6 gene as a genetic trait of a GC experience. Moreover, the identification of PB IgM+IgD+CD27+ B cells clonally related to GC-derived IgG+ memory B cells with shared and distinct IgV gene mutations demonstrates the GC origin also of the former subset. These findings provide genetic evidence for a GC derivation of somatically muta... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021995 Mon, 23 Nov 2009 23:26:36 +0100 3021995 http://www.medworm.com/index.php?rid=3021994&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2641%3Frss%3D1 B lymphocyte–intrinsic Toll-like receptor (TLR) signals amplify humoral immunity and can exacerbate autoimmune diseases. We identify a new mechanism by which TLR signals may contribute to autoimmunity and chronic inflammation. We show that TLR4 signaling enhances B lymphocyte trafficking into lymph nodes (LNs), induces B lymphocyte clustering and interactions within LN follicles, leads to sustained in vivo B cell proliferation, overcomes the restriction that limits the access of nonantigen-activated B cells to germinal center dark zones, and enhances the generation of memory and plasma cells. Intravital microscopy and in vivo tracking studies of B cells transferred to recipient mice revealed that TLR4-activated, but not nonstimulated, B cells accumulated within the dark zones of pree... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021994 Mon, 23 Nov 2009 23:26:36 +0100 3021994 http://www.medworm.com/index.php?rid=3021993&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2625%3Frss%3D1 The H2AX core histone variant is phosphorylated in chromatin around DNA double strand breaks (DSBs) and functions through unknown mechanisms to suppress antigen receptor locus translocations during V(D)J recombination. Formation of chromosomal coding joins and suppression of translocations involves the ataxia telangiectasia mutated and DNA-dependent protein kinase catalytic subunit serine/threonine kinases, each of which phosphorylates H2AX along cleaved antigen receptor loci. Using Abelson transformed pre–B cell lines, we find that H2AX is not required for coding join formation within chromosomal V(D)J recombination substrates. Yet we show that H2AX is phosphorylated along cleaved Ig DNA strands and prevents their separation in G1 phase cells and their progression into chromosome br... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021993 Mon, 23 Nov 2009 23:26:36 +0100 3021993 http://www.medworm.com/index.php?rid=3021992&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2613%3Frss%3D1 Both class switch recombination (CSR) and somatic hypermutation (SHM) require transcription and the trans-acting factor activation-induced cytidine deaminase (AID), and must be up-regulated during antigen-dependent differentiation of B lymphocytes. To test the role of the heavy chain 3' enhancers in both CSR and SHM, we used a BAC transgene of the entire heavy chain constant region locus. Using Cre-loxP recombination to delete a 28-kb region that contains the four known 3' heavy chain enhancers, we isolated lines of BAC transgenic mice with an intact heavy chain locus and paired lines in the same chromosomal insertion site lacking the 3' enhancers. Intact heavy chain transgenes undergo CSR to all heavy chain genes and mutate their transgenic VDJ exon. In paired transgenes lacking the 3' en... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021992 Mon, 23 Nov 2009 23:26:36 +0100 3021992 http://www.medworm.com/index.php?rid=3021991&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2603%3Frss%3D1 During somatic hypermutation (SHM), B cells introduce mutations into their immunoglobulin genes to generate high affinity antibodies. Current models suggest a separation in the generation of G/C transversions by the Ung2-dependent pathway and the generation of A/T mutations by the Msh2/ubiquitinated proliferating cell nuclear antigen (PCNA-Ub)–dependent pathway. It is currently unknown whether these pathways compete to initiate mutagenesis and whether PCNA-Ub functions downstream of Ung2. Furthermore, these models do not explain why mice lacking Msh2 have a more than twofold reduction in the total mutation frequency. Our data indicate that PCNA-Ub is required for A/T mutagenesis downstream of both Msh2 and Ung2. Furthermore, we provide evidence that both pathways are noncompetitive t... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021991 Mon, 23 Nov 2009 23:26:36 +0100 3021991 http://www.medworm.com/index.php?rid=3021990&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2593%3Frss%3D1 Mucosal vaccination via the respiratory tract can elicit protective immunity in animal infection models, but the underlying mechanisms are still poorly understood. We show that a single intranasal application of the replication-deficient modified vaccinia virus Ankara, which is widely used as a recombinant vaccination vector, results in prominent induction of bronchus-associated lymphoid tissue (BALT). Although initial peribronchiolar infiltrations, characterized by the presence of dendritic cells (DCs) and few lymphocytes, can be found 4 d after virus application, organized lymphoid structures with segregated B and T cell zones are first observed at day 8. After intratracheal application, in vitro–differentiated, antigen-loaded DCs rapidly migrate into preformed BALT and efficiently... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021990 Mon, 23 Nov 2009 23:26:36 +0100 3021990 http://www.medworm.com/index.php?rid=3021989&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2583%3Frss%3D1 We report on a genome-wide linkage search for loci that have an impact on TST reactivity, which is defined either as zero versus nonzero (TST-BINa) or as extent of TST in millimeters (TST–quantitative trait locus [QTL]) in a panel of 128 families, including 350 siblings, from an area of South Africa hyperendemic for TB. We detected a major locus (TST1) on chromosomal region 11p14 (P = 1.4 x 10–5), which controls TST-BINa, with a lack of responsiveness indicating T cell–independent resistance to M. tuberculosis. We also detected a second major locus (TST2) on chromosomal region 5p15 (P < 10–5), which controls TST-QTL or the intensity of T cell–mediated delayed type hypersensitivity (DTH) to tuberculin. Fine mapping of this region identified SLC6A3, encoding ... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021989 Mon, 23 Nov 2009 23:26:36 +0100 3021989 http://www.medworm.com/index.php?rid=3021988&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2580%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021988 Mon, 23 Nov 2009 23:26:36 +0100 3021988 http://www.medworm.com/index.php?rid=3021987&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2579-a%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021987 Mon, 23 Nov 2009 23:26:36 +0100 3021987 http://www.medworm.com/index.php?rid=3021986&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2579%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021986 Mon, 23 Nov 2009 23:26:36 +0100 3021986 http://www.medworm.com/index.php?rid=3021985&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2578-b%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021985 Mon, 23 Nov 2009 23:26:36 +0100 3021985 http://www.medworm.com/index.php?rid=3021984&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2578-a%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021984 Mon, 23 Nov 2009 23:26:36 +0100 3021984 http://www.medworm.com/index.php?rid=3021983&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F12%2F2578%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=3021983 Mon, 23 Nov 2009 23:26:36 +0100 3021983 http://www.medworm.com/index.php?rid=2930066&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F11%2F2573%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=2930066 Mon, 26 Oct 2009 16:19:01 +0100 2930066 http://www.medworm.com/index.php?rid=2930065&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F11%2F2557%3Frss%3D1 Human killer cell immunoglobulin-like receptors (KIRs) are distinguished by expansion of activating KIR2DS, whose ligands and functions remain poorly understood. The oldest, most prevalent KIR2DS is KIR2DS4, which is represented by a variable balance between "full-length" and "deleted" forms. We find that full-length 2DS4 is a human histocompatibility leukocyte antigen (HLA) class I receptor that binds specifically to subsets of C1+ and C2+ HLA-C and to HLA-A*11, whereas deleted 2DS4 is nonfunctional. Activation of 2DS4+ NKL cells was achieved with A*1102 as ligand, which differs from A*1101 by unique substitution of lysine 19 for glutamate, but not with A*1101 or HLA-C. Distinguishing KIR2DS4 from other KIR2DS is the proline–valine motif at positions 71–72, which is shared wit... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=2930065 Mon, 26 Oct 2009 16:19:01 +0100 2930065 http://www.medworm.com/index.php?rid=2930064&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F11%2F2543%3Frss%3D1 Of the potent lipid inflammatory mediators comprising the cysteinyl leukotrienes (LTs; LTC4, LTD4, and LTE4), only LTE4 is stable and abundant in vivo. Although LTE4 shows negligible activity at the type 1 and 2 receptors for cys-LTs (CysLT1R and CysLT2R), it is a powerful inducer of mucosal eosinophilia and airway hyperresponsiveness in humans with asthma. We show that the adenosine diphosphate (ADP)–reactive purinergic (P2Y12) receptor is required for LTE4-mediated pulmonary inflammation. P2Y12 receptor expression permits LTE4 -induced activation of extracellular signal-regulated kinase in Chinese hamster ovary cells and permits chemokine and prostaglandin D2 production by LAD2 cells, a human mast cell line. P2Y12 receptor expression by LAD2 cells is required for competition betwee... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=2930064 Mon, 26 Oct 2009 16:19:01 +0100 2930064 http://www.medworm.com/index.php?rid=2930063&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F11%2F2527%3Frss%3D1 ZAP-70 is critical for T cell receptor (TCR) signaling. Tyrosine to phenylalanine mutations of Y315 and Y319 in ZAP-70 suggest these residues function to recruit downstream effector molecules, but mutagenesis and crystallization studies reveal that these residues also play an important role in autoinhibition ZAP-70. To address the importance of the scaffolding function, we generated a zap70 mutant mouse (YYAA mouse) with Y315 and Y319 both mutated to alanines. These YYAA mice reveal that the scaffolding function is important for normal development and function. Moreover, the YYAA mice have many similarities to a previously identified ZAP-70 mutant mouse, SKG, which harbors a distinct hypomorphic mutation. Both YYAA and SKG mice have impaired T cell development and hyporesponsiveness to TCR... The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=2930063 Mon, 26 Oct 2009 16:19:01 +0100 2930063 http://www.medworm.com/index.php?rid=2930062&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F11%2F2511%3Frss%3D1 We report that isolated neonatal porcine SC, administered alone in highly biocompatible microcapsules, led to diabetes prevention and reversion in the respective 88 and 81% of overtly diabetic (nonobese diabetic [NOD]) mice, with no need for additional β cell or insulin therapy. The effect was associated with restoration of systemic immune tolerance and detection of functional pancreatic islets that consisted of glucose-responsive and insulin-secreting cells. Curative effects by SC were strictly dependent on efficient tryptophan metabolism in the xenografts, leading to TGF-β–dependent emergence of autoantigen-specific regulatory T cells and recovery of β cell function in the diabetic recipients. (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=2930062 Mon, 26 Oct 2009 16:19:01 +0100 2930062 http://www.medworm.com/index.php?rid=2930038&cid=s_33862_49_f&fid=33862&url=http%3A%2F%2Fjem.rupress.org%2Fcgi%2Fcontent%2Fshort%2F206%2F11%2Fi26%3Frss%3D1 (Source: The Journal of Experimental Medicine) The Journal of Experimental Medicine journals http://www.medworm.com/rss/comments.php?id=2930038 Mon, 26 Oct 2009 16:19:01 +0100 2930038