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Nature Immunology

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https://www.readbyqxmd.com/read/28218746/early-transcriptional-and-epigenetic-regulation-of-cd8-t-cell-differentiation-revealed-by-single-cell-rna-sequencing
#1
Boyko Kakaradov, Janilyn Arsenio, Christella E Widjaja, Zhaoren He, Stefan Aigner, Patrick J Metz, Bingfei Yu, Ellen J Wehrens, Justine Lopez, Stephanie H Kim, Elina I Zuniga, Ananda W Goldrath, John T Chang, Gene W Yeo
During microbial infection, responding CD8(+) T lymphocytes differentiate into heterogeneous subsets that together provide immediate and durable protection. To elucidate the dynamic transcriptional changes that underlie this process, we applied a single-cell RNA-sequencing approach and analyzed individual CD8(+) T lymphocytes sequentially throughout the course of a viral infection in vivo. Our analyses revealed a striking transcriptional divergence among cells that had undergone their first division and identified previously unknown molecular determinants that controlled the fate specification of CD8(+) T lymphocytes...
February 20, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28218745/human-%C3%AE-%C3%AE-t-cells-are-quickly-reconstituted-after-stem-cell-transplantation-and-show-adaptive-clonal-expansion-in-response-to-viral-infection
#2
Sarina Ravens, Christian Schultze-Florey, Solaiman Raha, Inga Sandrock, Melanie Drenker, Linda Oberdörfer, Annika Reinhardt, Inga Ravens, Maleen Beck, Robert Geffers, Constantin von Kaisenberg, Michael Heuser, Felicitas Thol, Arnold Ganser, Reinhold Förster, Christian Koenecke, Immo Prinz
To investigate how the human γδ T cell pool is shaped during ontogeny and how it is regenerated after transplantation of hematopoietic stem cells (HSCs), we applied an RNA-based next-generation sequencing approach to monitor the dynamics of the repertoires of γδ T cell antigen receptors (TCRs) before and after transplantation in a prospective cohort study. We found that repertoires of rearranged genes encoding γδ TCRs (TRG and TRD) in the peripheral blood of healthy adults were stable over time. Although a large fraction of human TRG repertoires consisted of public sequences, the TRD repertoires were private...
February 20, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28192418/defining-the-antibody-cross-reactome-directed-against-the-influenza-virus-surface-glycoproteins
#3
Raffael Nachbagauer, Angela Choi, Ariana Hirsh, Irina Margine, Sayaka Iida, Aldo Barrera, Marcela Ferres, Randy A Albrecht, Adolfo García-Sastre, Nicole M Bouvier, Kimihito Ito, Rafael A Medina, Peter Palese, Florian Krammer
Infection with influenza virus induces antibodies to the viral surface glycoproteins hemagglutinin and neuraminidase, and these responses can be broadly protective. To assess the breadth and magnitude of antibody responses, we sequentially infected mice, guinea pigs and ferrets with divergent H1N1 or H3N2 subtypes of influenza virus. We measured antibody responses by ELISA of an extensive panel of recombinant glycoproteins representing the viral diversity in nature. Guinea pigs developed high titers of broadly cross-reactive antibodies; mice and ferrets exhibited narrower humoral responses...
February 13, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28192417/defining-b-cell-immunodominance-to-viruses
#4
Davide Angeletti, James S Gibbs, Matthew Angel, Ivan Kosik, Heather D Hickman, Gregory M Frank, Suman R Das, Adam K Wheatley, Madhu Prabhakaran, David J Leggat, Adrian B McDermott, Jonathan W Yewdell
Immunodominance (ID) defines the hierarchical immune response to competing antigens in complex immunogens. Little is known regarding B cell and antibody ID despite its importance in immunity to viruses and other pathogens. We show that B cells and serum antibodies from inbred mice demonstrate a reproducible ID hierarchy to the five major antigenic sites in the influenza A virus hemagglutinin globular domain. The hierarchy changed as the immune response progressed, and it was dependent on antigen formulation and delivery...
February 13, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28166218/critical-role-of-irf1-and-batf-in-forming-chromatin-landscape-during-type-1-regulatory-cell-differentiation
#5
Katarzyna Karwacz, Emily R Miraldi, Maria Pokrovskii, Asaf Madi, Nir Yosef, Ivo Wortman, Xi Chen, Aaron Watters, Nicholas Carriero, Amit Awasthi, Aviv Regev, Richard Bonneau, Dan Littman, Vijay K Kuchroo
Type 1 regulatory T cells (Tr1 cells) are induced by interleukin-27 (IL-27) and have critical roles in the control of autoimmunity and resolution of inflammation. We found that the transcription factors IRF1 and BATF were induced early on after treatment with IL-27 and were required for the differentiation and function of Tr1 cells in vitro and in vivo. Epigenetic and transcriptional analyses revealed that both transcription factors influenced chromatin accessibility and expression of the genes required for Tr1 cell function...
February 6, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28166217/drugs-and-drug-like-molecules-can-modulate-the-function-of-mucosal-associated-invariant-t-cells
#6
Andrew N Keller, Sidonia B G Eckle, Weijun Xu, Ligong Liu, Victoria A Hughes, Jeffrey Y W Mak, Bronwyn S Meehan, Troi Pediongco, Richard W Birkinshaw, Zhenjun Chen, Huimeng Wang, Criselle D'Souza, Lars Kjer-Nielsen, Nicholas A Gherardin, Dale I Godfrey, Lyudmila Kostenko, Alexandra J Corbett, Anthony W Purcell, David P Fairlie, James McCluskey, Jamie Rossjohn
The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists...
February 6, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28114290/the-transcription-factor-musculin-promotes-the-unidirectional-development-of-peripheral-treg-cells-by-suppressing-the-th2-transcriptional-program
#7
Chuan Wu, Zuojia Chen, Valerie Dardalhon, Sheng Xiao, Theresa Thalhamer, Mengyang Liao, Asaf Madi, Rafael F Franca, Timothy Han, Mohammed Oukka, Vijay Kuchroo
Although master transcription factors (TFs) are key to the development of specific T cell subsets, whether additional transcriptional regulators are induced by the same stimuli that dominantly repress the development of other, non-specific T cell lineages has not been fully elucidated. Through the use of regulatory T cells (Treg cells) induced by transforming growth factor-β (TGF-β), we identified the TF musculin (MSC) as being critical for the development of induced Treg cells (iTreg cells) by repression of the T helper type 2 (TH2) transcriptional program...
January 23, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28092375/postprandial-macrophage-derived-il-1%C3%AE-stimulates-insulin-and-both-synergistically-promote-glucose-disposal-and-inflammation
#8
Erez Dror, Elise Dalmas, Daniel T Meier, Stephan Wueest, Julien Thévenet, Constanze Thienel, Katharina Timper, Thierry M Nordmann, Shuyang Traub, Friederike Schulze, Flurin Item, David Vallois, Francois Pattou, Julie Kerr-Conte, Vanessa Lavallard, Thierry Berney, Bernard Thorens, Daniel Konrad, Marianne Böni-Schnetzler, Marc Y Donath
The deleterious effect of chronic activation of the IL-1β system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1β in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1β, in a glucose-dependent manner. Subsequently, IL-1β contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1β signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma...
January 16, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28135254/the-igm-receptor-fc%C3%AE-r-limits-tonic-bcr-signaling-by-regulating-expression-of-the-igm-bcr
#9
Trang T T Nguyen, Kathrin Kläsener, Christa Zürn, Patricia A Castillo, Ingrid Brust-Mascher, Denise M Imai, Charles L Bevins, Colin Reardon, Michael Reth, Nicole Baumgarth
The FcμR receptor for the crystallizable fragment (Fc) of immunoglobulin M (IgM) can function as a cell-surface receptor for secreted IgM on a variety of cell types. We found here that FcμR was also expressed in the trans-Golgi network of developing B cells, where it constrained transport of the IgM-isotype BCR (IgM-BCR) but not of the IgD-isotype BCR (IgD-BCR). In the absence of FcμR, the surface expression of IgM-BCR was increased, which resulted in enhanced tonic BCR signaling. B-cell-specific deficiency in FcμR enhanced the spontaneous differentiation of B-1 cells, which resulted in increased serum concentrations of natural IgM and dysregulated homeostasis of B-2 cells; this caused the spontaneous formation of germinal centers, increased titers of serum autoantibodies and excessive accumulation of B cells...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28135253/alternative-pathway-for-the-development-of-v%C3%AE-14-nkt-cells-directly-from-cd4-cd8-thymocytes-that-bypasses-the-cd4-cd8-stage
#10
Nyambayar Dashtsoodol, Tomokuni Shigeura, Minako Aihara, Ritsuko Ozawa, Satoshi Kojo, Michishige Harada, Takaho A Endo, Takashi Watanabe, Osamu Ohara, Masaru Taniguchi
Although invariant Vα14(+) natural killer T cells (NKT cells) are thought to be generated from CD4(+)CD8(+) double-positive (DP) thymocytes, the developmental origin of CD4(-)CD8(-) double-negative (DN) NKT cells still remains unresolved. Here we provide definitive genetic evidence obtained, through studies of mice with DP-stage-specific ablation of expression of the gene encoding the recombinase component RAG-2 (Rag2) and by a fate-mapping approach, that supports the proposal of the existence of an alternative developmental pathway through which a fraction of DN NKT cells with strong T-helper-type-1 (TH1)-biased and cytotoxic characteristics develop from late DN-stage thymocytes, bypassing the DP stage...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28135252/the-transcriptional-regulator-aire-binds-to-and-activates-super-enhancers
#11
Kushagra Bansal, Hideyuki Yoshida, Christophe Benoist, Diane Mathis
Aire is a transcription factor that controls T cell tolerance by inducing the expression of a large repertoire of genes specifically in thymic stromal cells. It interacts with scores of protein partners of diverse functional classes. We found that Aire and some of its partners, notably those implicated in the DNA-damage response, preferentially localized to and activated long chromatin stretches that were overloaded with transcriptional regulators, known as super-enhancers. We also identified topoisomerase 1 as a cardinal Aire partner that colocalized on super-enhancers and was required for the interaction of Aire with all of its other associates...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28114292/gsk3-is-a-metabolic-checkpoint-regulator-in-b-cells
#12
Julia Jellusova, Matthew H Cato, John R Apgar, Parham Ramezani-Rad, Charlotte R Leung, Cindi Chen, Adam D Richardson, Elaine M Conner, Robert J Benschop, James R Woodgett, Robert C Rickert
B cells predominate in a quiescent state until an antigen is encountered, which results in rapid growth, proliferation and differentiation of the B cells. These distinct cell states are probably accompanied by differing metabolic needs, yet little is known about the metabolic control of B cell fate. Here we show that glycogen synthase kinase 3 (Gsk3) is a metabolic sensor that promotes the survival of naive recirculating B cells by restricting cell mass accumulation. In antigen-driven responses, Gsk3 was selectively required for regulation of B cell size, mitochondrial biogenesis, glycolysis and production of reactive oxygen species (ROS), in a manner mediated by the co-stimulatory receptor CD40...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28114291/a-sestrin-dependent-erk-jnk-p38-mapk-activation-complex-inhibits-immunity-during-aging
#13
Alessio Lanna, Daniel C O Gomes, Bojana Muller-Durovic, Thomas McDonnell, David Escors, Derek W Gilroy, Jun Hee Lee, Michael Karin, Arne N Akbar
Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery...
January 23, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28092373/chronic-signaling-via-the-metabolic-checkpoint-kinase-mtorc1-induces-macrophage-granuloma-formation-and-marks-sarcoidosis-progression
#14
Monika Linke, Ha Thi Thanh Pham, Karl Katholnig, Thomas Schnöller, Anne Miller, Florian Demel, Birgit Schütz, Margit Rosner, Boris Kovacic, Nyamdelger Sukhbaatar, Birgit Niederreiter, Stephan Blüml, Peter Kuess, Veronika Sexl, Mathias Müller, Mario Mikula, Wolfram Weckwerth, Arvand Haschemi, Martin Susani, Markus Hengstschläger, Michael J Gambello, Thomas Weichhart
The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28092372/direct-control-of-regulatory-t-cells-by-keratinocytes
#15
Mariko Kashiwagi, Junichi Hosoi, Jen-Feng Lai, Janice Brissette, Steven F Ziegler, Bruce A Morgan, Katia Georgopoulos
Environmental challenges to epithelial cells trigger gene expression changes that elicit context-appropriate immune responses. We found that the chromatin remodeler Mi-2β controls epidermal homeostasis by regulating the genes involved in keratinocyte and immune-cell activation to maintain an inactive state. Mi-2β depletion resulted in rapid deployment of both a pro-inflammatory and an immunosuppressive response in the skin. A key target of Mi-2β in keratinocytes is the pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP)...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28068307/transitional-b-cells-commit-to-marginal-zone-b-cell-fate-by-taok3-mediated-surface-expression-of-adam10
#16
Hamida Hammad, Matthias Vanderkerken, Philippe Pouliot, Kim Deswarte, Wendy Toussaint, Karl Vergote, Lana Vandersarren, Sophie Janssens, Ioanna Ramou, Savvas N Savvides, Jody J Haigh, Rudi Hendriks, Manfred Kopf, Katleen Craessaerts, Bart de Strooper, John F Kearney, Daniel H Conrad, Bart N Lambrecht
Notch2 and B cell antigen receptor (BCR) signaling determine whether transitional B cells become marginal zone B (MZB) or follicular B (FoB) cells in the spleen, but it is unknown how these pathways are related. We generated Taok3(-/-) mice, lacking the serine/threonine kinase Taok3, and found cell-intrinsic defects in the development of MZB but not FoB cells. Type 1 transitional (T1) B cells required Taok3 to rapidly respond to ligation by the Notch ligand Delta-like 1. BCR ligation by endogenous or exogenous ligands induced the surface expression of the metalloproteinase ADAM10 on T1 B cells in a Taok3-dependent manner...
March 2017: Nature Immunology
https://www.readbyqxmd.com/read/28198833/neuroimmune-interactions-astrocytes
#17
Ioana Visan
No abstract text is available yet for this article.
February 15, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28198832/cytof-analysis-of-anti-tumor-responses
#18
Laurie A Dempsey
No abstract text is available yet for this article.
February 15, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28198831/anti-dengue-igg1
#19
Laurie A Dempsey
No abstract text is available yet for this article.
February 15, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28198830/-final-common-pathway-of-human-cancer-immunotherapy-targeting-random-somatic-mutations
#20
REVIEW
Eric Tran, Paul F Robbins, Steven A Rosenberg
Effective clinical cancer immunotherapies, such as administration of the cytokine IL-2, adoptive cell transfer (ACT) and the recent success of blockade of the checkpoint modulators CTLA-4 and PD-1, have been developed without clear identification of the immunogenic targets expressed by human cancers in vivo. Immunotherapy of patients with cancer through the use of ACT with autologous lymphocytes has provided an opportunity to directly investigate the antigen recognition of lymphocytes that mediate cancer regression in humans...
February 15, 2017: Nature Immunology
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