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Nature Immunology

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https://www.readbyqxmd.com/read/27893701/the-signaling-adaptor-traf1-negatively-regulates-toll-like-receptor-signaling-and-this-underlies-its-role-in-rheumatic-disease
#1
Ali A Abdul-Sater, Maria I Edilova, Derek L Clouthier, Achire Mbanwi, Elisabeth Kremmer, Tania H Watts
TRAF1 is a signaling adaptor known for its role in tumor necrosis factor receptor-induced cell survival. Here we show that monocytes from healthy human subjects with a rheumatoid arthritis-associated single-nucleotide polymorphism (SNP) in the TRAF1 gene express less TRAF1 protein but greater amounts of inflammatory cytokines in response to lipopolysaccharide (LPS). The TRAF1 MATH domain binds directly to three components of the linear ubiquitination (LUBAC) complex, SHARPIN, HOIP and HOIL-1, to interfere with the recruitment and linear ubiquitination of NEMO...
November 28, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27893700/trans-presentation-of-il-6-by-dendritic-cells-is-required-for-the-priming-of-pathogenic-th17-cells
#2
Sylvia Heink, Nir Yogev, Christoph Garbers, Marina Herwerth, Lilian Aly, Christiane Gasperi, Veronika Husterer, Andrew L Croxford, Katja Möller-Hackbarth, Harald S Bartsch, Karl Sotlar, Stefan Krebs, Tommy Regen, Helmut Blum, Bernhard Hemmer, Thomas Misgeld, Thomas F Wunderlich, Juan Hidalgo, Mohamed Oukka, Stefan Rose-John, Marc Schmidt-Supprian, Ari Waisman, Thomas Korn
The cellular sources of interleukin 6 (IL-6) that are relevant for differentiation of the TH17 subset of helper T cells remain unclear. Here we used a novel strategy for the conditional deletion of distinct IL-6-producing cell types to show that dendritic cells (DCs) positive for the signaling regulator Sirpα were essential for the generation of pathogenic TH17 cells. Using their IL-6 receptor α-chain (IL-6Rα), Sirpα(+) DCs trans-presented IL-6 to T cells during the process of cognate interaction. While ambient IL-6 was sufficient to suppress the induction of expression of the transcription factor Foxp3 in T cells, trans-presentation of IL-6 by DC-bound IL-6Rα (called 'IL-6 cluster signaling' here) was needed to prevent premature induction of interferon-γ (IFN-γ) expression in T cells and to generate pathogenic TH17 cells in vivo...
November 28, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27869820/tet-proteins-regulate-the-lineage-specification-and-tcr-mediated-expansion-of-inkt-cells
#3
Ageliki Tsagaratou, Edahí González-Avalos, Sini Rautio, James P Scott-Browne, Susan Togher, William A Pastor, Ellen V Rothenberg, Lukas Chavez, Harri Lähdesmäki, Anjana Rao
TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4(+)CD8(+) double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK...
November 21, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27869819/a-cycle-of-zap70-kinase-activation-and-release-from-the-tcr-amplifies-and-disperses-antigenic-stimuli
#4
Zachary B Katz, Lucie Novotná, Amy Blount, Björn F Lillemeier
Cell-surface-receptor pathways amplify weak, rare and local stimuli to induce cellular responses. This task is accomplished despite signaling components that segregate into nanometer-scale membrane domains. Here we describe a 'catch-and-release' mechanism that amplified and dispersed stimuli by releasing activated kinases from receptors lacking intrinsic catalytic activity. Specifically, we discovered a cycle of recruitment, activation and release for Zap70 kinases at phosphorylated T cell antigen receptors (TCRs)...
November 21, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27869818/tcr%C3%AE-tcr%C3%AE-pairing-controls-recognition-of-cd1d-and-directs-the-development-of-adipose-nkt-cells
#5
Joshua A Vieth, Joy Das, Fanomezana M Ranaivoson, Davide Comoletti, Lisa K Denzin, Derek B Sant'Angelo
The interaction between the T cell antigen receptor (TCR) expressed by natural killer T cells (NKT cells) and the antigen-presenting molecule CD1d is distinct from interactions between the TCR and major histocompatibility complex (MHC). Our molecular modeling suggested that a hydrophobic patch created after TCRα-TCRβ pairing has a role in maintaining the conformation of the NKT cell TCR. Disruption of this patch ablated recognition of CD1d by the NKT cell TCR but not interactions of the TCR with MHC. Partial disruption of the patch, while permissive to the recognition of CD1d, significantly altered NKT cell development, which resulted in the selective accumulation of adipose-tissue-resident NKT cells...
November 21, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27869817/the-aryl-hydrocarbon-receptor-ahr-links-atopic-dermatitis-and-air-pollution-via-induction-of-the-neurotrophic-factor-artemin
#6
Takanori Hidaka, Eisaku Ogawa, Eri H Kobayashi, Takafumi Suzuki, Ryo Funayama, Takeshi Nagashima, Taku Fujimura, Setsuya Aiba, Keiko Nakayama, Ryuhei Okuyama, Masayuki Yamamoto
Atopic dermatitis is increasing worldwide in correlation with air pollution. Various organic components of pollutants activate the transcription factor AhR (aryl hydrocarbon receptor). Through the use of AhR-CA mice, whose keratinocytes express constitutively active AhR and that develop atopic-dermatitis-like phenotypes, we identified Artn as a keratinocyte-specific AhR target gene whose product (the neurotrophic factor artemin) was responsible for epidermal hyper-innervation that led to hypersensitivity to pruritus...
November 21, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27841869/gradients-of-the-signaling-lipid-s1p-in-lymph-nodes-position-natural-killer-cells-and-regulate-their-interferon-%C3%AE-response
#7
Victoria Fang, V Sai Chaluvadi, Willy D Ramos-Perez, Alejandra Mendoza, Audrey Baeyens, Richard Rivera, Jerold Chun, Michael Cammer, Susan R Schwab
The lymph node periphery is an important site for many immunological functions, from pathogen containment to the differentiation of helper T cells, yet the cues that position cells in this region are largely undefined. Here, through the use of a reporter for the signaling lipid S1P (sphingosine 1-phosphate), we found that cells sensed higher concentrations of S1P in the medullary cords than in the T cell zone and that the S1P transporter SPNS2 on lymphatic endothelial cells generated this gradient. Natural killer (NK) cells are located at the periphery of the lymph node, predominantly in the medulla, and we found that expression of SPNS2, expression of the S1P receptor S1PR5 on NK cells, and expression of the chemokine receptor CXCR4 were all required for NK cell localization during homeostasis and rapid production of interferon-γ by NK cells after challenge...
November 14, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27820810/a-myc-dependent-division-timer-complements-a-cell-death-timer-to-regulate-t-cell-and-b-cell-responses
#8
Susanne Heinzel, Tran Binh Giang, Andrey Kan, Julia M Marchingo, Bryan K Lye, Lynn M Corcoran, Philip D Hodgkin
T lymphocytes and B lymphocytes integrate activating signals to control the size of their proliferative response. Here we report that such control was achieved by timed changes in the production rate of cell-cycle-regulating proto-oncoprotein Myc, with division cessation occurring when Myc levels fell below a critical threshold. The changing pattern of the level of Myc was not affected by cell division, which identified the regulating mechanism as a cell-intrinsic, heritable temporal controller. Overexpression of Myc in stimulated T cells and B cells did not sustain cell proliferation indefinitely, as a separate 'time-to-die' mechanism, also heritable, was programmed after lymphocyte activation and led to eventual cell loss...
November 7, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27820809/regulation-of-autoantibody-activity-by-the-il-23-th17-axis-determines-the-onset-of-autoimmune-disease
#9
René Pfeifle, Tobias Rothe, Natacha Ipseiz, Hans U Scherer, Stephan Culemann, Ulrike Harre, Jochen A Ackermann, Martina Seefried, Arnd Kleyer, Stefan Uderhardt, Benjamin Haugg, Axel J Hueber, Patrick Daum, Gordon F Heidkamp, Changrong Ge, Sybille Böhm, Anja Lux, Wolfgang Schuh, Iryna Magorivska, Kutty S Nandakumar, Erik Lönnblom, Christoph Becker, Diana Dudziak, Manfred Wuhrer, Yoann Rombouts, Carolien A Koeleman, René Toes, Thomas H Winkler, Rikard Holmdahl, Martin Herrmann, Stephan Blüml, Falk Nimmerjahn, Georg Schett, Gerhard Krönke
The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the TH17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, TH17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged...
November 7, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27721430/usp15-regulates-type-i-interferon-response-and-is-required-for-pathogenesis-of-neuroinflammation
#10
Sabrina Torre, Maria J Polyak, David Langlais, Nassima Fodil, James M Kennedy, Irena Radovanovic, Joanne Berghout, Gabriel A Leiva-Torres, Connie M Krawczyk, Subburaj Ilangumaran, Karen Mossman, Chen Liang, Klaus-Peter Knobeloch, Luke M Healy, Jack Antel, Nathalie Arbour, Alexandre Prat, Jacek Majewski, Mark Lathrop, Silvia M Vidal, Philippe Gros
Genes and pathways in which inactivation dampens tissue inflammation present new opportunities for understanding the pathogenesis of common human inflammatory diseases, including inflammatory bowel disease, rheumatoid arthritis and multiple sclerosis. We identified a mutation in the gene encoding the deubiquitination enzyme USP15 (Usp15(L749R)) that protected mice against both experimental cerebral malaria (ECM) induced by Plasmodium berghei and experimental autoimmune encephalomyelitis (EAE). Combining immunophenotyping and RNA sequencing in brain (ECM) and spinal cord (EAE) revealed that Usp15(L749R)-associated resistance to neuroinflammation was linked to dampened type I interferon responses in situ...
October 10, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27668800/ccl19-ccr7-dependent-reverse-transendothelial-migration-of-myeloid-cells-clears-chlamydia-muridarum-from-the-arterial-intima
#11
Mark Roufaiel, Eric Gracey, Allan Siu, Su-Ning Zhu, Andrew Lau, Hisham Ibrahim, Marwan Althagafi, Kelly Tai, Sharon J Hyduk, Kateryna O Cybulsky, Sherine Ensan, Angela Li, Rickvinder Besla, Henry M Becker, Haiyan Xiao, Sanjiv A Luther, Robert D Inman, Clinton S Robbins, Jenny Jongstra-Bilen, Myron I Cybulsky
Regions of the normal arterial intima predisposed to atherosclerosis are sites of ongoing monocyte trafficking and also contain resident myeloid cells with features of dendritic cells. However, the pathophysiological roles of these cells are poorly understood. Here we found that intimal myeloid cells underwent reverse transendothelial migration (RTM) into the arterial circulation after systemic stimulation of pattern-recognition receptors (PRRs). This process was dependent on expression of the chemokine receptor CCR7 and its ligand CCL19 by intimal myeloid cells...
September 26, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27668799/a-three-stage-intrathymic-development-pathway-for-the-mucosal-associated-invariant-t-cell-lineage
#12
Hui-Fern Koay, Nicholas A Gherardin, Anselm Enders, Liyen Loh, Laura K Mackay, Catarina F Almeida, Brendan E Russ, Claudia A Nold-Petry, Marcel F Nold, Sammy Bedoui, Zhenjun Chen, Alexandra J Corbett, Sidonia B G Eckle, Bronwyn Meehan, Yves d'Udekem, Igor E Konstantinov, Martha Lappas, Ligong Liu, Chris C Goodnow, David P Fairlie, Jamie Rossjohn, Mark M Chong, Katherine Kedzierska, Stuart P Berzins, Gabrielle T Belz, James McCluskey, Adam P Uldrich, Dale I Godfrey, Daniel G Pellicci
Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization...
September 26, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27618552/glioma-induced-inhibition-of-caspase-3-in-microglia-promotes-a-tumor-supportive-phenotype
#13
Xianli Shen, Miguel A Burguillos, Ahmed M Osman, Jeroen Frijhoff, Alejandro Carrillo-Jiménez, Sachie Kanatani, Martin Augsten, Dalel Saidi, Johanna Rodhe, Edel Kavanagh, Anthony Rongvaux, Vilma Rraklli, Ulrika Nyman, Johan Holmberg, Arne Östman, Richard A Flavell, Antonio Barragan, Jose Luis Venero, Klas Blomgren, Bertrand Joseph
Glioma cells recruit and exploit microglia (the resident immune cells of the brain) for their proliferation and invasion ability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype has remained elusive. We found that glioma-induced microglia conversion was coupled to a reduction in the basal activity of microglial caspase-3 and increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and that inhibition of caspase-3 regulated microglial tumor-supporting function...
September 12, 2016: Nature Immunology
https://www.readbyqxmd.com/read/27798619/protective-neutralizing-influenza-antibody-response-in-the-absence-of-t-follicular-helper-cells
#14
Kosuke Miyauchi, Akiko Sugimoto-Ishige, Yasuyo Harada, Yu Adachi, Yoshiko Usami, Tomohiro Kaji, Kentaro Inoue, Hideki Hasegawa, Takashi Watanabe, Atsushi Hijikata, Satoshi Fukuyama, Tadashi Maemura, Mariko Okada-Hatakeyama, Osamu Ohara, Yoshihiro Kawaoka, Yoshimasa Takahashi, Toshitada Takemori, Masato Kubo
Virus infection induces the development of T follicular helper (TFH) and T helper 1 (TH1) cells. Although TFH cells are important in anti-viral humoral immunity, the contribution of TH1 cells to a protective antibody response remains unknown. We found that IgG2 antibodies predominated in the response to vaccination with inactivated influenza A virus (IAV) and were responsible for protective immunity to lethal challenge with pathogenic H5N1 and pandemic H1N1 IAV strains, even in mice that lacked TFH cells and germinal centers...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27798618/heme-drives-hemolysis-induced-susceptibility-to-infection-via-disruption-of-phagocyte-functions
#15
Rui Martins, Julia Maier, Anna-Dorothea Gorki, Kilian V M Huber, Omar Sharif, Philipp Starkl, Simona Saluzzo, Federica Quattrone, Riem Gawish, Karin Lakovits, Michael C Aichinger, Branka Radic-Sarikas, Charles-Hugues Lardeau, Anastasiya Hladik, Ana Korosec, Markus Brown, Kari Vaahtomeri, Michelle Duggan, Dontscho Kerjaschki, Harald Esterbauer, Jacques Colinge, Stephanie C Eisenbarth, Thomas Decker, Keiryn L Bennett, Stefan Kubicek, Michael Sixt, Giulio Superti-Furga, Sylvia Knapp
Hemolysis drives susceptibility to bacterial infections and predicts poor outcome from sepsis. These detrimental effects are commonly considered to be a consequence of heme-iron serving as a nutrient for bacteria. We employed a Gram-negative sepsis model and found that elevated heme levels impaired the control of bacterial proliferation independently of heme-iron acquisition by pathogens. Heme strongly inhibited phagocytosis and the migration of human and mouse phagocytes by disrupting actin cytoskeletal dynamics via activation of the GTP-binding Rho family protein Cdc42 by the guanine nucleotide exchange factor DOCK8...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27798617/fibroblastic-reticular-cells-regulate-intestinal-inflammation-via-il-15-mediated-control-of-group-1-ilcs
#16
Cristina Gil-Cruz, Christian Perez-Shibayama, Lucas Onder, Qian Chai, Jovana Cupovic, Hung-Wei Cheng, Mario Novkovic, Philipp A Lang, Markus B Geuking, Kathy D McCoy, Shinya Abe, Guangwei Cui, Koichi Ikuta, Elke Scandella, Burkhard Ludewig
Fibroblastic reticular cells (FRCs) of secondary lymphoid organs form distinct niches for interaction with hematopoietic cells. We found here that production of the cytokine IL-15 by FRCs was essential for the maintenance of group 1 innate lymphoid cells (ILCs) in Peyer's patches and mesenteric lymph nodes. Moreover, FRC-specific ablation of the innate immunological sensing adaptor MyD88 unleashed IL-15 production by FRCs during infection with an enteropathogenic virus, which led to hyperactivation of group 1 ILCs and substantially altered the differentiation of helper T cells...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27798616/neutrophils-license-inkt-cells-to-regulate-self-reactive-mouse-b-cell-responses
#17
Thomas Hägglöf, Saikiran K Sedimbi, Jennifer L Yates, Roham Parsa, Briana Hauff Salas, Robert A Harris, Elizabeth A Leadbetter, Mikael C I Karlsson
The innate responsiveness of the immune system is important not only for quick responses to pathogens but also for the initiation and shaping of the subsequent adaptive immune response. Activation via the cytokine IL-18, a product of inflammasomes, gives rise to a rapid response that includes the production of self-reactive antibodies. As increased concentrations of this cytokine are found in inflammatory diseases, we investigated the origin of the B cell response and its regulation. We identified an accumulation of B cell-helper neutrophils in the spleen that interacted with innate-type invariant natural killer T cells (iNKT cells) to regulate B cell responses...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27776110/e3-ubiquitin-ligase-rnf128-promotes-innate-antiviral-immunity-through-k63-linked-ubiquitination-of-tbk1
#18
Guanhua Song, Bingyu Liu, Zhihui Li, Haifeng Wu, Peng Wang, Kai Zhao, Guosheng Jiang, Lei Zhang, Chengjiang Gao
TBK1 is essential for interferon-β (IFN-β) production and innate antiviral immunity. Here we identified the T cell anergy-related E3 ubiquitin ligase RNF128 as a positive regulator of TBK1 activation. RNF128 directly interacted with TBK1 through its protease-associated (PA) domain and catalyzed the K63-linked polyubiquitination of TBK1, which led to TBK1 activation, IRF3 activation and IFN-β production. Deficiency of RNF128 expression attenuated IRF3 activation, IFN-β production and innate antiviral immune responses to RNA and DNA viruses, in vitro and in vivo...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27776109/sall1-is-a-transcriptional-regulator-defining-microglia-identity-and-function
#19
Anne Buttgereit, Iva Lelios, Xueyang Yu, Melissa Vrohlings, Natalie R Krakoski, Emmanuel L Gautier, Ryuichi Nishinakamura, Burkhard Becher, Melanie Greter
Microglia are the resident macrophages of the central nervous system (CNS). Gene expression profiling has identified Sall1, which encodes a transcriptional regulator, as a microglial signature gene. We found that Sall1 was expressed by microglia but not by other members of the mononuclear phagocyte system or by other CNS-resident cells. Using Sall1 for microglia-specific gene targeting, we found that the cytokine receptor CSF1R was involved in the maintenance of adult microglia and that the receptor for the cytokine TGF-β suppressed activation of microglia...
December 2016: Nature Immunology
https://www.readbyqxmd.com/read/27776108/programs-for-the-persistence-vigilance-and-control-of-human-cd8-lung-resident-memory-t-cells
#20
Pleun Hombrink, Christina Helbig, Ronald A Backer, Berber Piet, Anna E Oja, Regina Stark, Giso Brasser, Aldo Jongejan, René E Jonkers, Benjamin Nota, Onur Basak, Hans C Clevers, Perry D Moerland, Derk Amsen, René A W van Lier
Tissue-resident memory T cells (TRM cells) in the airways mediate protection against respiratory infection. We characterized TRM cells expressing integrin αE (CD103) that reside within the epithelial barrier of human lungs. These cells had specialized profiles of chemokine receptors and adhesion molecules, consistent with their unique localization. Lung TRM cells were poised for rapid responsiveness by constitutive expression of deployment-ready mRNA encoding effector molecules, but they also expressed many inhibitory regulators, suggestive of programmed restraint...
December 2016: Nature Immunology
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