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Correction: Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils
Vol. 216, No. 11, November 4, 2019. 10.1084/jem.20180371. The authors regret that in their original paper, the TNBS+anti-Ly6G+T2AA image in Fig. 8 D was incorrect as a result of an error during figure preparation. In... (Source: The Journal of Experimental Medicine)
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Ohayon, D., De Chiara, A., My-Chan Dang, P., Thieblemont, N., Chatfield, S., Marzaioli, V., Burgener, S. S., Mocek, J., Candalh, C., Pintard, C., Tacnet-Delorme, P., Renault, G., Lagoutte, I., Favier, M., Walker, F., Hurtado-Nedelec, M., Desplancq, D., We Tags: Corrections Source Type: research

Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis
Prostate cancer (PCa) metastasizes selectively to bone through unknown mechanisms. In the current study, we identified exosome-mediated transfer of pyruvate kinase M2 (PKM2) from PCa cells into bone marrow stromal cells (BMSCs) as a novel mechanism through which primary tumor-derived exosomes promote premetastatic niche formation. We found that PKM2 up-regulates BMSC CXCL12 production in a HIF-1α-dependent fashion, which subsequently enhances PCa seeding and growth in the bone marrow. Furthermore, serum-derived exosomes from patients with either primary PCa or PCa metastasis, as opposed to healthy men, reveal that in...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Dai, J., Escara-Wilke, J., Keller, J. M., Jung, Y., Taichman, R. S., Pienta, K. J., Keller, E. T. Tags: Solid Tumors Articles Source Type: research

Creatine uptake regulates CD8 T cell antitumor immunity
T cells demand massive energy to combat cancer; however, the metabolic regulators controlling antitumor T cell immunity have just begun to be unveiled. When studying nutrient usage of tumor-infiltrating immune cells in mice, we detected a sharp increase of the expression of a CrT (Slc6a8) gene, which encodes a surface transporter controlling the uptake of creatine into a cell. Using CrT knockout mice, we showed that creatine uptake deficiency severely impaired antitumor T cell immunity. Supplementing creatine to WT mice significantly suppressed tumor growth in multiple mouse tumor models, and the combination of creatine su...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Di Biase, S., Ma, X., Wang, X., Yu, J., Wang, Y.-C., Smith, D. J., Zhou, Y., Li, Z., Kim, Y. J., Clarke, N., To, A., Yang, L. Tags: Tumor Immunology, Metabolism Articles Source Type: research

Intratumoral delivery of RIG-I agonist SLR14 induces robust antitumor responses
In this study, we tested the antitumor activity of a unique RIG-I agonist, stem loop RNA (SLR) 14. In the immunogenic tumor models, we observed significant tumor growth delay and an extended survival in SLR14-treated mice. SLR14 also greatly improved antitumor efficacy of anti-PD1 antibody over single-agent treatment. SLR14 was mainly taken up by CD11b+ myeloid cells in the tumor microenvironment, and many genes associated with immune defense were significantly up-regulated after treatment, accompanied by increase in the number of CD8+ T lymphocytes, NK cells, and CD11b+ cells in SLR14-treated tumors. Strikingly, SLR14 dra...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Jiang, X., Muthusamy, V., Fedorova, O., Kong, Y., Kim, D. J., Bosenberg, M., Pyle, A. M., Iwasaki, A. Tags: Tumor Immunology Articles Source Type: research

Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR
The role of lipids in inflammasome activation remains underappreciated. The phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein–coupled seven-transmembrane receptor (PAFR). PAF is associated with a number of inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function remains to be fully elucidated. We show that multiple PAF isoforms and PAF-like lipids can activate the inflammasome, resulting in IL-1β and IL-18 maturation. This is dependent on NLRP3, ASC, caspase-1, and NEK7, but not on NLRC4, NLRP1, NLRP6, AIM2, caspas...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Deng, M., Guo, H., Tam, J. W., Johnson, B. M., Brickey, W. J., New, J. S., Lenox, A., Shi, H., Golenbock, D. T., Koller, B. H., McKinnon, K. P., Beutler, B., Ting, J. P.- Y. Tags: Innate Immunity and Inflammation Articles Source Type: research

TGF-{beta} signaling controls Foxp3 methylation and T reg cell differentiation by modulating Uhrf1 activity
Regulatory T (T reg) cells are required for the maintenance of immune homeostasis. Both TGF-β signaling and epigenetic modifications are important for Foxp3 induction, but how TGF-β signaling participates in the epigenetic regulation of Foxp3 remains largely unknown. Here we showed that T cell–specific ablation of Uhrf1 resulted in T reg–biased differentiation in TCR-stimulated naive T cells in the absence of TGF-β signaling, and these Foxp3+ T cells had a suppressive function. Adoptive transfer of Uhrf1–/– naive T cells could significantly suppress colitis due to increased iT reg cel...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Sun, X., Cui, Y., Feng, H., Liu, H., Liu, X. Tags: Articles Source Type: research

Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells
Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand–expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persist...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Rodriguez, R., Fournier, B., Cordeiro, D. J., Winter, S., Izawa, K., Martin, E., Boutboul, D., Lenoir, C., Fraitag, S., Kracker, S., Watts, T. H., Picard, C., Bruneau, J., Callebaut, I., Fischer, A., Neven, B., Latour, S. Tags: Immunodeficiency Articles Source Type: research

A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function
Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Lam, M. T., Coppola, S., Krumbach, O. H. F., Prencipe, G., Insalaco, A., Cifaldi, C., Brigida, I., Zara, E., Scala, S., Di Cesare, S., Martinelli, S., Di Rocco, M., Pascarella, A., Niceta, M., Pantaleoni, F., Ciolfi, A., Netter, P., Carisey, A. F., Diehl, Tags: Innate Immunity and Inflammation, Hematopoiesis, Human Disease Genetics Articles Source Type: research

A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2-mediated inflammation
Group 2 innate lymphoid cells (ILC2s) possess indispensable roles during type 2–mediated inflammatory diseases. Although their physiological and detrimental immune functions seem to depend on the anatomical compartment they reside, their tissue tropism and the molecular and immunological processes regulating the self-renewal of the local pool of ILC2s in the context of inflammation or infection are incompletely understood. Here, we analyzed the role of the CC-chemokine receptor CCR8 for the biological functions of ILC2s. In vitro and in vivo experiments indicated that CCR8 is in comparison to the related molecule CCR...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Knipfer, L., Schulz-Kuhnt, A., Kindermann, M., Greif, V., Symowski, C., Voehringer, D., Neurath, M. F., Atreya, I., Wirtz, S. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense, Mucosal Immunology Articles Source Type: research

CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways
Resident memory T cells (TRM cells) are an important first-line defense against respiratory pathogens, but the unique contributions of lung TRM cell populations to protective immunity and the factors that govern their localization to different compartments of the lung are not well understood. Here, we show that airway and interstitial TRM cells have distinct effector functions and that CXCR6 controls the partitioning of TRM cells within the lung by recruiting CD8 TRM cells to the airways. The absence of CXCR6 significantly decreases airway CD8 TRM cells due to altered trafficking of CXCR6–/– cells within the lu...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Wein, A. N., McMaster, S. R., Takamura, S., Dunbar, P. R., Cartwright, E. K., Hayward, S. L., McManus, D. T., Shimaoka, T., Ueha, S., Tsukui, T., Masumoto, T., Kurachi, M., Matsushima, K., Kohlmeier, J. E. Tags: Infectious Disease and Host Defense, Mucosal Immunology Articles Source Type: research

Interstitial-resident memory CD8+ T cells sustain frontline epithelial memory in the lung
Populations of CD8+ lung-resident memory T (TRM) cells persist in the interstitium and epithelium (airways) following recovery from respiratory virus infections. While it is clear that CD8+ TRM cells in the airways are dynamically maintained via the continuous recruitment of new cells, there is a vigorous debate about whether tissue-circulating effector memory T (TEM) cells are the source of these newly recruited cells. Here we definitively demonstrate that CD8+ TRM cells in the lung airways are not derived from TEM cells in the circulation, but are seeded continuously by TRM cells from the lung interstitium. This process ...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Takamura, S., Kato, S., Motozono, C., Shimaoka, T., Ueha, S., Matsuo, K., Miyauchi, K., Masumoto, T., Katsushima, A., Nakayama, T., Tomura, M., Matsushima, K., Kubo, M., Miyazawa, M. Tags: Mucosal Immunology Brief Definitive Reports Source Type: research

A homozygous SFTPA1 mutation drives necroptosis of type II alveolar epithelial cells in patients with idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by scattered fibrotic lesions in the lungs. The pathogenesis and genetic basis of IPF remain poorly understood. Here, we show that a homozygous missense mutation in SFTPA1 caused IPF in a consanguineous Japanese family. The mutation in SFTPA1 disturbed the secretion of SFTPA1 protein. Sftpa1 knock-in (Sftpa1-KI) mice that harbored the same mutation as patients spontaneously developed pulmonary fibrosis that was accelerated by influenza virus infection. Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II (AEII) cells with phosphoryla...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Takezaki, A., Tsukumo, S.-i., Setoguchi, Y., Ledford, J. G., Goto, H., Hosomichi, K., Uehara, H., Nishioka, Y., Yasutomo, K. Tags: Innate Immunity and Inflammation, Human Disease Genetics Brief Definitive Reports Source Type: research

ILC2s mediate systemic innate protection by priming mucus production at distal mucosal sites
Host immunity to parasitic nematodes requires the generation of a robust type 2 cytokine response, characterized by the production of interleukin 13 (IL-13), which drives expulsion. Here, we show that infection with helminths in the intestine also induces an ILC2-driven, IL-13–dependent goblet cell hyperplasia and increased production of mucins (Muc5b and Muc5ac) at distal sites, including the lungs and other mucosal barrier sites. Critically, we show that type 2 priming of lung tissue through increased mucin production inhibits the progression of a subsequent lung migratory helminth infection and limits its transit ...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Campbell, L., Hepworth, M. R., Whittingham-Dowd, J., Thompson, S., Bancroft, A. J., Hayes, K. S., Shaw, T. N., Dickey, B. F., Flamar, A.-L., Artis, D., Schwartz, D. A., Evans, C. M., Roberts, I. S., Thornton, D. J., Grencis, R. K. Tags: Innate Immunity and Inflammation, Infectious Disease and Host Defense, Mucosal Immunology Brief Definitive Reports Source Type: research

Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids
Patients treated with immune checkpoint blockade (ICB) sometimes experience immune-related adverse events (irAEs), requiring immuno-suppressive drugs such as corticosteroids despite the possibility that immunosuppression may impair the antitumor effects of ICB. Here, we address the dilemma of using corticosteroids for the treatment of irAEs induced by ICB. ICB augments neoantigen-specific CD8+ T cell responses, resulting in tumor regression. In our model, simultaneous, but not late, administration of corticosteroids impaired antitumor responses with reduction of CD8+ T cell proliferation. Secondary challenge using tumors w...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Tokunaga, A., Sugiyama, D., Maeda, Y., Warner, A. B., Panageas, K. S., Ito, S., Togashi, Y., Sakai, C., Wolchok, J. D., Nishikawa, H. Tags: Tumor Immunology Brief Definitive Reports Source Type: research

Modulation of the fungal mycobiome is regulated by the chitin-binding receptor FIBCD1
Host–microbiota interactions are critical in regulating mammalian health and disease. In addition to bacteria, parasites, and viruses, beneficial communities of fungi (the mycobiome) are important modulators of immune- and tissue-homeostasis. Chitin is a major component of the fungal cell wall, and fibrinogen C containing domain 1 (FIBCD1) is a chitin-binding protein; however, the role of this molecule in influencing host–mycobiome interactions in vivo has never been examined. Here, we identify direct binding of FIBCD1 to intestinal-derived fungi and demonstrate that epithelial-specific expression of FIBCD1 res...
Source: The Journal of Experimental Medicine - December 1, 2019 Category: Internal Medicine Authors: Moeller, J. B., Leonardi, I., Schlosser, A., Flamar, A.-L., Bessman, N. J., Putzel, G. G., Thomsen, T., Hammond, M., Jepsen, C. S., Skjodt, K., Füchtbauer, E.-M., Farber, D. L., Sorensen, G. L., Iliev, I. D., Holmskov, U., Artis, D. Tags: Innate Immunity and Inflammation, Mucosal Immunology Brief Definitive Reports Source Type: research