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  • Rapid chromatin repression by Aire provides precise control of immune tolerance
    Nat. Immunol. (IF 21.506) Pub Date : 2018-01-15
    Andrew S. Koh, Erik L. Miller, Jason D. Buenrostro, David M. Moskowitz, Jing Wang, William J. Greenleaf, Howard Y. Chang, Gerald R. Crabtree

    Aire mediates the expression of tissue-specific antigens in thymic epithelial cells to promote tolerance against self-reactive T lymphocytes. However, the mechanism that allows expression of tissue-specific genes at levels that prevent harm is unknown. Here we show that Brg1 generates accessibility at tissue-specific loci to impose central tolerance. We found that Aire has an intrinsic repressive function that restricts chromatin accessibility and opposes Brg1 across the genome. Aire exerted this repressive influence within minutes after recruitment to chromatin and restrained the amplitude of active transcription. Disease-causing mutations that impair Aire-induced activation also impair the protein’s repressive function, which indicates dual roles for Aire. Together, Brg1 and Aire fine-tune the expression of tissue-specific genes at levels that prevent toxicity yet promote immune tolerance.

    更新日期:2018-01-15
  • Aged polymorphonuclear leukocytes cause fibrotic interstitial lung disease in the absence of regulation by B cells
    Nat. Immunol. (IF 21.506) Pub Date : 2018-01-15
    Jung Hwan Kim, John Podstawka, Yuefei Lou, Lu Li, Esther K. S. Lee, Maziar Divangahi, Björn Petri, Frank R. Jirik, Margaret M. Kelly, Bryan G. Yipp

    Pulmonary immunity requires tight regulation, as interstitial inflammation can compromise gas exchange and lead to respiratory failure. Here we found a greater number of aged CD11bhiL-selectinloCXCR4+ polymorphonuclear leukocytes (PMNs) in lung vasculature than in the peripheral circulation. Using pulmonary intravital microscopy, we observed lung PMNs physically interacting with B cells via β2 integrins; this initiated neutrophil apoptosis, which led to macrophage-mediated clearance. Genetic deletion of B cells led to the accumulation of aged PMNs in the lungs without systemic inflammation, which caused pathological fibrotic interstitial lung disease that was attenuated by the adoptive transfer of B cells or depletion of PMNs. Thus, the lungs are an intermediary niche in the PMN lifecycle wherein aged PMNs are regulated by B cells, which restrains their potential to cause pulmonary pathology.

    更新日期:2018-01-15
  • Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory
    Nat. Immunol. (IF 21.506) Pub Date : 2018-01-08
    Lalit K. Beura, Jason S. Mitchell, Emily A. Thompson, Jason M. Schenkel, Javed Mohammed, Sathi Wijeyesinghe, Raissa Fonseca, Brandon J. Burbach, Heather D. Hickman, Vaiva Vezys, Brian T. Fife, David Masopust

    CD8+ T cell immunosurveillance dynamics influence the outcome of intracellular infections and cancer. Here we used two-photon intravital microscopy to visualize the responses of CD8+ resident memory T cells (TRM cells) within the reproductive tracts of live female mice. We found that mucosal TRM cells were highly motile, but paused and underwent in situ division after local antigen challenge. TRM cell reactivation triggered the recruitment of recirculating memory T cells that underwent antigen-independent TRM cell differentiation in situ. However, the proliferation of pre-existing TRM cells dominated the local mucosal recall response and contributed most substantially to the boosted secondary TRM cell population. We observed similar results in skin. Thus, TRM cells can autonomously regulate the expansion of local immunosurveillance independently of central memory or proliferation in lymphoid tissue.

    更新日期:2018-01-08
  • Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses
    Nat. Immunol. (IF 21.506) Pub Date : 2018-01-08
    Simone L. Park, Ali Zaid, Jyh Liang Hor, Susan N. Christo, Julia E. Prier, Brooke Davies, Yannick O. Alexandre, Julia L. Gregory, Tiffany A. Russell, Thomas Gebhardt, Francis R. Carbone, David C. Tscharke, William R. Heath, Scott N. Mueller, Laura K. Mackay

    Although tissue-resident memory T cells (TRM cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin TRM cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary TRM cells formed from pre-existing TRM cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander TRM cells were generated in the skin without displacement of the pre-existing TRM cell pool. Thus, pre-existing skin TRM cell populations are not displaced after subsequent infections, which enables multiple TRM cell specificities to be stably maintained within the tissue.

    更新日期:2018-01-08
  • The ER membrane adaptor ERAdP senses the bacterial second messenger c-di-AMP and initiates anti-bacterial immunity
    Nat. Immunol. (IF 21.506) Pub Date : 2018-01-01
    Pengyan Xia, Shuo Wang, Zhen Xiong, Xiaoxiao Zhu, Buqing Ye, Ying Du, Shu Meng, Yuan Qu, Jing Liu, Guangxia Gao, Yong Tian, Zusen Fan

    Cyclic diadenylate monophosphate (c-di-AMP) is secreted by bacteria as a secondary messenger. How immune cells detect c-di-AMP and initiate anti-bacterial immunity remains unknown. We found that the endoplasmic reticulum (ER) membrane adaptor ERAdP acts as a direct sensor for c-di-AMP. ERAdP-deficient mice were highly susceptible to Listeria monocytogenes infection and exhibited reduced pro-inflammatory cytokines. Mechanistically, c-di-AMP bound to the C-terminal domain of ERAdP, which in turn led to dimerization of ERAdP, resulting in association with and activation of the kinase TAK1. TAK1 activation consequently initiated activation of the transcription factor NF-κB to induce the production of pro-inflammatory cytokines in innate immune cells. Moreover, double-knockout of ERAdP and TAK1 resulted in heightened susceptibility to L. monocytogenes infection. Thus, ERAdP-mediated production of pro-inflammatory cytokines is critical for controlling bacterial infection.

    更新日期:2018-01-01
  • Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1
    Nat. Immunol. (IF 21.506) Pub Date : 2018-01-01
    Charise Garber, Michael J. Vasek, Lauren L. Vollmer, Tony Sun, Xiaoping Jiang, Robyn S. Klein

    Memory impairment following West Nile virus neuroinvasive disease (WNND) is associated with loss of hippocampal synapses with lack of recovery. Adult neurogenesis and synaptogenesis are fundamental features of hippocampal repair, which suggests that viruses affect these processes. Here, in an established model of WNND-induced cognitive dysfunction, transcriptional profiling revealed alterations in the expression of genes encoding molecules that limit adult neurogenesis, including interleukin 1 (IL-1). Mice that had recovered from WNND exhibited fewer neuroblasts and increased astrogenesis without recovery of hippocampal neurogenesis at 30 d. Analysis of cytokine production in microglia and astrocytes isolated ex vivo revealed that the latter were the predominant source of IL-1. Mice deficient in the IL-1 receptor IL-1R1 and that had recovered from WNND exhibited normal neurogenesis, recovery of presynaptic termini and resistance to spatial learning defects, the last of which likewise occurred after treatment with an IL-1R1 antagonist. Thus, ‘preferential’ generation of proinflammatory astrocytes impaired the homeostasis of neuronal progenitor cells via expression of IL-1; this might underlie the long-term cognitive consequences of WNND but also provides a therapeutic target.

    更新日期:2018-01-01
  • Oxeiptosis, a ROS-induced caspase-independent apoptosis-like cell-death pathway
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-18
    Cathleen Holze, Chloé Michaudel, Claire Mackowiak, Darya A. Haas, Christian Benda, Philipp Hubel, Friederike L. Pennemann, Daniel Schnepf, Jennifer Wettmarshausen, Marianne Braun, Daisy W. Leung, Gaya K. Amarasinghe, Fabiana Perocchi, Peter Staeheli, Bernhard Ryffel, Andreas Pichlmair

    Reactive oxygen species (ROS) are generated by virus-infected cells; however, the physiological importance of ROS generated under these conditions is unclear. Here we found that the inflammation and cell death induced by exposure of mice or cells to sources of ROS were not altered in the absence of canonical ROS-sensing pathways or known cell-death pathways. ROS-induced cell-death signaling involved interactions among the cellular ROS sensor and antioxidant factor KEAP1, the phosphatase PGAM5 and the proapoptotic factor AIFM1. Pgam5–/– mice showed exacerbated lung inflammation and proinflammatory cytokines in an ozone-exposure model. Similarly, challenge with influenza A virus led to increased infiltration of the virus, lymphocytic bronchiolitis and reduced survival of Pgam5–/– mice. This pathway, which we have called ‘oxeiptosis’, was a ROS-sensitive, caspase independent, non-inflammatory cell-death pathway and was important for protection against inflammation induced by ROS or ROS-generating agents such as viral pathogens.

    更新日期:2017-12-18
  • Scoring presentation
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-14
    Ioana Visan

    Scoring presentation Scoring presentation, Published online: 14 December 2017; doi:10.1038/s41590-017-0015-9 Scoring presentation

    更新日期:2017-12-15
  • STAT5B in RICD
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-14
    Laurie A Dempsey

    STAT5B in RICD STAT5B in RICD, Published online: 14 December 2017; doi:10.1038/s41590-017-0018-6 STAT5B in RICD

    更新日期:2017-12-15
  • Another way to not get eaten
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-14
    Cheng Cheng Zhang, Yang-Xin Fu

    Another way to not get eaten Another way to not get eaten, Published online: 14 December 2017; doi:10.1038/s41590-017-0009-7 A previously unknown role is identified for a pathway that involves major histocompatibility complex class I and an inhibitory receptor, LILRB1, that regulates the phagocytosis of cancer cells by macrophages and contributes to resistance directed against the signal-regulatory protein CD47.

    更新日期:2017-12-15
  • Self-RNA sentinels signal viral invasion
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-14
    Andrew G. Bowie

    Self-RNA sentinels signal viral invasion Self-RNA sentinels signal viral invasion, Published online: 14 December 2017; doi:10.1038/s41590-017-0010-1 A new ‘alarm mechanism’ of the innate immune system that signals the presence of nuclear viruses involves the sensing of host 5S rRNA by RIG-I.

    更新日期:2017-12-15
  • Silent clearance
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-14
    Ioana Visan

    Silent clearance Silent clearance, Published online: 14 December 2017; doi:10.1038/s41590-017-0016-8 Silent clearance

    更新日期:2017-12-15
  • The twilight of immunity: emerging concepts in aging of the immune system
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-14
    Janko Nikolich-Žugich

    Immunosenescence is a series of age-related changes that affect the immune system and, with time, lead to increased vulnerability to infectious diseases. This Review addresses recent developments in the understanding of age-related changes that affect key components of immunity, including the effect of aging on cells of the (mostly adaptive) immune system, on soluble molecules that guide the maintenance and function of the immune system and on lymphoid organs that coordinate both the maintenance of lymphocytes and the initiation of immune responses. I further address the effect of the metagenome and exposome as key modifiers of immune-system aging and discuss a conceptual framework in which age-related changes in immunity might also affect the basic rules by which the immune system operates.

    更新日期:2017-12-15
  • Assaulting the microbiota
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-14
    Zoltan Fehervari

    Assaulting the microbiota Assaulting the microbiota, Published online: 14 December 2017; doi:10.1038/s41590-017-0020-z Assaulting the microbiota

    更新日期:2017-12-15
  • Author Correction: Charles D. Surh 1960–2017
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-08
    Janko Nikolich-Žugich

    Author Correction: Charles D. Surh 1960–2017 Author Correction: Charles D. Surh 1960–2017, Published online: 08 December 2017; doi:10.1038/s41590-017-0025-7 Author Correction: Charles D. Surh 1960–2017

    更新日期:2017-12-10
  • Diversification of human plasmacytoid predendritic cells in response to a single stimulus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-04
    Solana G. Alculumbre, Violaine Saint-André, Jeremy Di Domizio, Pablo Vargas, Philemon Sirven, Pierre Bost, Mathieu Maurin, Paolo Maiuri, Maxime Wery, Mabel San Roman, Léa Savey, Maxime Touzot, Benjamin Terrier, David Saadoun, Curdin Conrad, Michel Gilliet, Antonin Morillon, Vassili Soumelis

    Innate immune cells adjust to microbial and inflammatory stimuli through a process termed environmental plasticity, which links a given individual stimulus to a unique activated state. Here, we report that activation of human plasmacytoid predendritic cells (pDCs) with a single microbial or cytokine stimulus triggers cell diversification into three stable subpopulations (P1–P3). P1-pDCs (PD-L1+CD80–) displayed a plasmacytoid morphology and specialization for type I interferon production. P3-pDCs (PD-L1–CD80+) adopted a dendritic morphology and adaptive immune functions. P2-pDCs (PD-L1+CD80+) displayed both innate and adaptive functions. Each subpopulation expressed a specific coding- and long-noncoding-RNA signature and was stable after secondary stimulation. P1-pDCs were detected in samples from patients with lupus or psoriasis. pDC diversification was independent of cell divisions or preexisting heterogeneity within steady-state pDCs but was controlled by a TNF autocrine and/or paracrine communication loop. Our findings reveal a novel mechanism for diversity and division of labor in innate immune cells.

    更新日期:2017-12-05
  • Emerging viral diseases from a vaccinology perspective: preparing for the next pandemic
    Nat. Immunol. (IF 21.506) Pub Date : 2017-12-03
    Barney S. Graham, Nancy J. Sullivan

    Emerging infectious diseases will continue to threaten public health and are sustained by global commerce, travel and disruption of ecological systems. Most pandemic threats are caused by viruses from either zoonotic sources or vector-borne sources. Developing better ways to anticipate and manage the ongoing microbial challenge will be critical for achieving the United Nations Sustainable Development Goals and, conversely, each such goal will affect the ability to control infectious diseases. Here we discuss how technology can be applied effectively to better prepare for and respond to new viral diseases with a focus on new paradigms for vaccine development.

    更新日期:2017-12-04
  • Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-27
    Jessica J. Chiang, Konstantin M. J. Sparrer, Michiel van Gent, Charlotte Lässig, Teng Huang, Nikolaus Osterrieder, Karl-Peter Hopfner, Michaela U. Gack

    The sensor RIG-I detects double-stranded RNA derived from RNA viruses. Although RIG-I is also known to have a role in the antiviral response to DNA viruses, physiological RNA species recognized by RIG-I during infection with a DNA virus are largely unknown. Using next-generation RNA sequencing (RNAseq), we found that host-derived RNAs, most prominently 5S ribosomal RNA pseudogene 141 (RNA5SP141), bound to RIG-I during infection with herpes simplex virus 1 (HSV-1). Infection with HSV-1 induced relocalization of RNA5SP141 from the nucleus to the cytoplasm, and virus-induced shutoff of host protein synthesis downregulated the abundance of RNA5SP141-interacting proteins, which allowed RNA5SP141 to bind RIG-I and induce the expression of type I interferons. Silencing of RNA5SP141 strongly dampened the antiviral response to HSV-1 and the related virus Epstein-Barr virus (EBV), as well as influenza A virus (IAV). Our findings reveal that antiviral immunity can be triggered by host RNAs that are unshielded following depletion of their respective binding proteins by the virus.

    更新日期:2017-11-28
  • Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-27
    Amira A. Barkal, Kipp Weiskopf, Kevin S. Kao, Sydney R. Gordon, Benyamin Rosental, Ying Y. Yiu, Benson M. George, Maxim Markovic, Nan G. Ring, Jonathan M. Tsai, Kelly M. McKenna, Po Yi Ho, Robin Z. Cheng, James Y. Chen, Layla J. Barkal, Aaron M. Ring, Irving L. Weissman, Roy L. Maute

    Exciting progress in the field of cancer immunotherapy has renewed the urgency of the need for basic studies of immunoregulation in both adaptive cell lineages and innate cell lineages. Here we found a central role for major histocompatibility complex (MHC) class I in controlling the phagocytic function of macrophages. Our results demonstrated that expression of the common MHC class I component β2-microglobulin (β2M) by cancer cells directly protected them from phagocytosis. We further showed that this protection was mediated by the inhibitory receptor LILRB1, whose expression was upregulated on the surface of macrophages, including tumor-associated macrophages. Disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo, which defines the MHC class I–LILRB1 signaling axis as an important regulator of the effector function of innate immune cells, a potential biomarker for therapeutic response to agents directed against the signal-regulatory protein CD47 and a potential target of anti-cancer immunotherapy.

    更新日期:2017-11-28
  • Viral unmasking of cellular 5S rRNA pseudogene transcripts induces RIG-I-mediated immunity
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-27
    Jessica J. Chiang, Konstantin M. J. Sparrer, Michiel van Gent, Charlotte Lässig, Teng Huang, Nikolaus Osterrieder, Karl-Peter Hopfner, Michaela U. Gack

    The sensor RIG-I detects double-stranded RNA derived from RNA viruses. Although RIG-I is also known to have a role in the antiviral response to DNA viruses, physiological RNA species recognized by RIG-I during infection with a DNA virus are largely unknown. Using next-generation RNA sequencing (RNAseq), we found that host-derived RNAs, most prominently 5S ribosomal RNA pseudogene 141 (RNA5SP141), bound to RIG-I during infection with herpes simplex virus 1 (HSV-1). Infection with HSV-1 induced relocalization of RNA5SP141 from the nucleus to the cytoplasm, and virus-induced shutoff of host protein synthesis downregulated the abundance of RNA5SP141-interacting proteins, which allowed RNA5SP141 to bind RIG-I and induce the expression of type I interferons. Silencing of RNA5SP141 strongly dampened the antiviral response to HSV-1 and the related virus Epstein-Barr virus (EBV), as well as influenza A virus (IAV). Our findings reveal that antiviral immunity can be triggered by host RNAs that are unshielded following depletion of their respective binding proteins by the virus.

    更新日期:2017-11-28
  • Engagement of MHC class I by the inhibitory receptor LILRB1 suppresses macrophages and is a target of cancer immunotherapy
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-27
    Amira A. Barkal, Kipp Weiskopf, Kevin S. Kao, Sydney R. Gordon, Benyamin Rosental, Ying Y. Yiu, Benson M. George, Maxim Markovic, Nan G. Ring, Jonathan M. Tsai, Kelly M. McKenna, Po Yi Ho, Robin Z. Cheng, James Y. Chen, Layla J. Barkal, Aaron M. Ring, Irving L. Weissman, Roy L. Maute

    Exciting progress in the field of cancer immunotherapy has renewed the urgency of the need for basic studies of immunoregulation in both adaptive cell lineages and innate cell lineages. Here we found a central role for major histocompatibility complex (MHC) class I in controlling the phagocytic function of macrophages. Our results demonstrated that expression of the common MHC class I component β2-microglobulin (β2M) by cancer cells directly protected them from phagocytosis. We further showed that this protection was mediated by the inhibitory receptor LILRB1, whose expression was upregulated on the surface of macrophages, including tumor-associated macrophages. Disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo, which defines the MHC class I–LILRB1 signaling axis as an important regulator of the effector function of innate immune cells, a potential biomarker for therapeutic response to agents directed against the signal-regulatory protein CD47 and a potential target of anti-cancer immunotherapy.

    更新日期:2017-11-28
  • Nuclear RNF2 inhibits interferon function by promoting K33-linked STAT1 disassociation from DNA
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-21
    Shuo Liu, Minghong Jiang, Wendie Wang, Wei Liu, Xiaoqi Song, Zhongfei Ma, Shikun Zhang, Lun Liu, Yin Liu, Xuetao Cao

    Prolonged activation of interferon–STAT1 signaling is closely related to inflammatory autoimmune disorders, and therefore the identification of negative regulators of these pathways is important. Through high-content screening of 115 mouse RING-domain E3 ligases, we identified the E3 ubiquitin ligase RNF2 as a potent inhibitor of interferon-dependent antiviral responses. RNF2 deficiency substantially enhanced interferon-stimulated gene (ISG) expression and antiviral responses. Mechanistically, nuclear RNF2 directly bound to STAT1 after interferon stimulation and increased K33-linked polyubiquitination of the DNA-binding domain of STAT1 at position K379, in addition to promoting the disassociation of STAT1/STAT2 from DNA and consequently suppressing ISG transcription. Our study provides insight into the regulation of interferon-dependent responses via a previously unrecognized post-translational modification of STAT1 in the nucleus.

    更新日期:2017-11-22
  • Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-21
    Dimitris Karamitros, Bilyana Stoilova, Zahra Aboukhalil, Fiona Hamey, Andreas Reinisch, Marina Samitsch, Lynn Quek, Georg Otto, Emmanouela Repapi, Jessica Doondeea, Batchimeg Usukhbayar, Julien Calvo, Stephen Taylor, Nicolas Goardon, Emmanuelle Six, Francoise Pflumio, Catherine Porcher, Ravindra Majeti, Berthold Göttgens, Paresh Vyas

    The hierarchy of human hemopoietic progenitor cells that produce lymphoid and granulocytic–monocytic (myeloid) lineages is unclear. Multiple progenitor populations produce lymphoid and myeloid cells, but they remain incompletely characterized. Here we demonstrated that lympho-myeloid progenitor populations in cord blood — lymphoid-primed multi-potential progenitors (LMPPs), granulocyte-macrophage progenitors (GMPs) and multi-lymphoid progenitors (MLPs) — were functionally and transcriptionally distinct and heterogeneous at the clonal level, with progenitors of many different functional potentials present. Although most progenitors had the potential to develop into only one mature cell type (‘uni-lineage potential’), bi- and rarer multi-lineage progenitors were present among LMPPs, GMPs and MLPs. Those findings, coupled with single-cell expression analyses, suggest that a continuum of progenitors execute lymphoid and myeloid differentiation, rather than only uni-lineage progenitors’ being present downstream of stem cells.

    更新日期:2017-11-22
  • Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-21
    Guoxiang Jin, Chuan Xu, Xian Zhang, Jie Long, Abdol Hossein Rezaeian, Chunfang Liu, Mark E. Furth, Steven Kridel, Boris Pasche, Xiu-Wu Bian, Hui-Kuan Lin

    Although deletion of certain autophagy-related genes has been associated with defects in hematopoiesis, it remains unclear whether hyperactivated mitophagy affects the maintenance and differentiation of hematopoietic stem cells (HSCs) and committed progenitor cells. Here we report that targeted deletion of the gene encoding the AAA+-ATPase Atad3a hyperactivated mitophagy in mouse hematopoietic cells. Affected mice showed reduced survival, severely decreased bone-marrow cellularity, erythroid anemia and B cell lymphopenia. Those phenotypes were associated with skewed differentiation of stem and progenitor cells and an enlarged HSC pool. Mechanistically, Atad3a interacted with the mitochondrial channel components Tom40 and Tim23 and served as a bridging factor to facilitate appropriate transportation and processing of the mitophagy protein Pink1. Loss of Atad3a caused accumulation of Pink1 and activated mitophagy. Notably, deletion of Pink1 in Atad3a-deficient mice significantly ‘rescued’ the mitophagy defect, which resulted in restoration of the progenitor and HSC pools. Our data indicate that Atad3a suppresses Pink1-dependent mitophagy and thereby serves a key role in hematopoietic homeostasis.

    更新日期:2017-11-22
  • Nuclear RNF2 inhibits interferon function by promoting K33-linked STAT1 disassociation from DNA
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-21
    Shuo Liu, Minghong Jiang, Wendie Wang, Wei Liu, Xiaoqi Song, Zhongfei Ma, Shikun Zhang, Lun Liu, Yin Liu, Xuetao Cao

    Prolonged activation of interferon–STAT1 signaling is closely related to inflammatory autoimmune disorders, and therefore the identification of negative regulators of these pathways is important. Through high-content screening of 115 mouse RING-domain E3 ligases, we identified the E3 ubiquitin ligase RNF2 as a potent inhibitor of interferon-dependent antiviral responses. RNF2 deficiency substantially enhanced interferon-stimulated gene (ISG) expression and antiviral responses. Mechanistically, nuclear RNF2 directly bound to STAT1 after interferon stimulation and increased K33-linked polyubiquitination of the DNA-binding domain of STAT1 at position K379, in addition to promoting the disassociation of STAT1/STAT2 from DNA and consequently suppressing ISG transcription. Our study provides insight into the regulation of interferon-dependent responses via a previously unrecognized post-translational modification of STAT1 in the nucleus.

    更新日期:2017-11-22
  • Single-cell analysis reveals the continuum of human lympho-myeloid progenitor cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-21
    Dimitris Karamitros, Bilyana Stoilova, Zahra Aboukhalil, Fiona Hamey, Andreas Reinisch, Marina Samitsch, Lynn Quek, Georg Otto, Emmanouela Repapi, Jessica Doondeea, Batchimeg Usukhbayar, Julien Calvo, Stephen Taylor, Nicolas Goardon, Emmanuelle Six, Francoise Pflumio, Catherine Porcher, Ravindra Majeti, Berthold Göttgens, Paresh Vyas

    The hierarchy of human hemopoietic progenitor cells that produce lymphoid and granulocytic–monocytic (myeloid) lineages is unclear. Multiple progenitor populations produce lymphoid and myeloid cells, but they remain incompletely characterized. Here we demonstrated that lympho-myeloid progenitor populations in cord blood — lymphoid-primed multi-potential progenitors (LMPPs), granulocyte-macrophage progenitors (GMPs) and multi-lymphoid progenitors (MLPs) — were functionally and transcriptionally distinct and heterogeneous at the clonal level, with progenitors of many different functional potentials present. Although most progenitors had the potential to develop into only one mature cell type (‘uni-lineage potential’), bi- and rarer multi-lineage progenitors were present among LMPPs, GMPs and MLPs. Those findings, coupled with single-cell expression analyses, suggest that a continuum of progenitors execute lymphoid and myeloid differentiation, rather than only uni-lineage progenitors’ being present downstream of stem cells.

    更新日期:2017-11-22
  • Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-21
    Guoxiang Jin, Chuan Xu, Xian Zhang, Jie Long, Abdol Hossein Rezaeian, Chunfang Liu, Mark E. Furth, Steven Kridel, Boris Pasche, Xiu-Wu Bian, Hui-Kuan Lin

    Although deletion of certain autophagy-related genes has been associated with defects in hematopoiesis, it remains unclear whether hyperactivated mitophagy affects the maintenance and differentiation of hematopoietic stem cells (HSCs) and committed progenitor cells. Here we report that targeted deletion of the gene encoding the AAA+-ATPase Atad3a hyperactivated mitophagy in mouse hematopoietic cells. Affected mice showed reduced survival, severely decreased bone-marrow cellularity, erythroid anemia and B cell lymphopenia. Those phenotypes were associated with skewed differentiation of stem and progenitor cells and an enlarged HSC pool. Mechanistically, Atad3a interacted with the mitochondrial channel components Tom40 and Tim23 and served as a bridging factor to facilitate appropriate transportation and processing of the mitophagy protein Pink1. Loss of Atad3a caused accumulation of Pink1 and activated mitophagy. Notably, deletion of Pink1 in Atad3a-deficient mice significantly ‘rescued’ the mitophagy defect, which resulted in restoration of the progenitor and HSC pools. Our data indicate that Atad3a suppresses Pink1-dependent mitophagy and thereby serves a key role in hematopoietic homeostasis.

    更新日期:2017-11-22
  • Suppression from beyond the grave
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Yosuke Togashi, Hiroyoshi Nishikawa

    Suppression from beyond the grave Suppression from beyond the grave, Published online: 16 November 2017; doi:10.1038/ni.3870 NatureArticleSnippet(type=standfirst, markup= Adenosine produced by apoptotic regulatory T cells (Treg cells) has a more important immunosuppressive role in the tumor microenvironment than that of live Treg cells. This discovery raises the possibility of novel strategies for cancer immunotherapy. , isJats=true)

    更新日期:2017-11-17
  • Feeling stressed? It might be your T cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Laura Strauss, Nikolaos Patsoukis, Vassiliki A Boussiotis

    Feeling stressed? It might be your T cells Feeling stressed? It might be your T cells, Published online: 16 November 2017; doi:10.1038/ni.3872 NatureArticleSnippet(type=standfirst, markup= Abolishing signals mediated by the inhibitory receptor PD-1 results in a systemic decrease in tryptophan and tyrosine, which leads to a striking deficiency in the neurotransmitters serotonin and dopamine in the brain and anxiety-like behavior and exacerbated fear. , isJats=true)

    更新日期:2017-11-17
  • Trained macrophages support hygiene hypothesis
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Bérengère de Laval, Michael H Sieweke

    Trained macrophages support hygiene hypothesis Trained macrophages support hygiene hypothesis, Published online: 16 November 2017; doi:10.1038/ni.3874 NatureArticleSnippet(type=standfirst, markup= Replacement of resident alveolar macrophages by monocyte-derived macrophages after herpesvirus infection protects against asthma. , isJats=true)

    更新日期:2017-11-17
  • Inflammatory lipids
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Laurie A. Dempsey

    Inflammatory lipids Inflammatory lipids, Published online: 16 November 2017; doi:10.1038/ni.3876

    更新日期:2017-11-17
  • Interferons control fungus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Zoltan Fehervari

    Interferons control fungus Interferons control fungus, Published online: 16 November 2017; doi:10.1038/ni.3880

    更新日期:2017-11-17
  • Corrigendum: The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Qingliang Zheng, Jin Hou, Ye Zhou, Zhenyang Li, Xuetao Cao

    Corrigendum: The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus Corrigendum: The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus, Published online: 16 November 2017; doi:10.1038/ni1217-1361a

    更新日期:2017-11-17
  • Tumor control
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Ioana Visan

    Tumor control Tumor control, Published online: 16 November 2017; doi:10.1038/ni.3878

    更新日期:2017-11-17
  • Charles D. Surh 1960–2017
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Janko Nikolich-Žugich

    Charles D. Surh 1960–2017 Charles D. Surh 1960–2017, Published online: 16 November 2017; doi:10.1038/ni.3871

    更新日期:2017-11-17
  • Suppression from beyond the grave
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Yosuke Togashi, Hiroyoshi Nishikawa

    Suppression from beyond the grave Suppression from beyond the grave, Published online: 16 November 2017; doi:10.1038/ni.3870 NatureArticleSnippet(type=standfirst, markup= Adenosine produced by apoptotic regulatory T cells (Treg cells) has a more important immunosuppressive role in the tumor microenvironment than that of live Treg cells. This discovery raises the possibility of novel strategies for cancer immunotherapy. , isJats=true)

    更新日期:2017-11-17
  • Feeling stressed? It might be your T cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Laura Strauss, Nikolaos Patsoukis, Vassiliki A Boussiotis

    Feeling stressed? It might be your T cells Feeling stressed? It might be your T cells, Published online: 16 November 2017; doi:10.1038/ni.3872 NatureArticleSnippet(type=standfirst, markup= Abolishing signals mediated by the inhibitory receptor PD-1 results in a systemic decrease in tryptophan and tyrosine, which leads to a striking deficiency in the neurotransmitters serotonin and dopamine in the brain and anxiety-like behavior and exacerbated fear. , isJats=true)

    更新日期:2017-11-17
  • Trained macrophages support hygiene hypothesis
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Bérengère de Laval, Michael H Sieweke

    Trained macrophages support hygiene hypothesis Trained macrophages support hygiene hypothesis, Published online: 16 November 2017; doi:10.1038/ni.3874 NatureArticleSnippet(type=standfirst, markup= Replacement of resident alveolar macrophages by monocyte-derived macrophages after herpesvirus infection protects against asthma. , isJats=true)

    更新日期:2017-11-17
  • Inflammatory lipids
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Laurie A. Dempsey

    Inflammatory lipids Inflammatory lipids, Published online: 16 November 2017; doi:10.1038/ni.3876

    更新日期:2017-11-17
  • Interferons control fungus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Zoltan Fehervari

    Interferons control fungus Interferons control fungus, Published online: 16 November 2017; doi:10.1038/ni.3880

    更新日期:2017-11-17
  • Corrigendum: The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Qingliang Zheng, Jin Hou, Ye Zhou, Zhenyang Li, Xuetao Cao

    Corrigendum: The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus Corrigendum: The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus, Published online: 16 November 2017; doi:10.1038/ni1217-1361a

    更新日期:2017-11-17
  • Tumor control
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Ioana Visan

    Tumor control Tumor control, Published online: 16 November 2017; doi:10.1038/ni.3878

    更新日期:2017-11-17
  • Charles D. Surh 1960–2017
    Nat. Immunol. (IF 21.506) Pub Date : 2017-11-16
    Janko Nikolich-Žugich

    Charles D. Surh 1960–2017 Charles D. Surh 1960–2017, Published online: 16 November 2017; doi:10.1038/ni.3871

    更新日期:2017-11-17
  • Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-30
    Tomasz Maj, Wei Wang, Joel Crespo, Hongjuan Zhang, Weimin Wang, Shuang Wei, Lili Zhao, Linda Vatan, Irene Shao, Wojciech Szeliga, Costas Lyssiotis, J Rebecca Liu, Ilona Kryczek, Weiping Zou

    Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor, Published online: 30 October 2017; doi:10.1038/ni.3868 NatureArticleSnippet(type=short-summary, markup= The tumor microenvironment represents a stressful cellular environment. Zou and colleagues show that Treg cells in tumors have heightened sensitivity to apoptosis, but unexpectedly this increases their suppressive potency. , isJats=true)

    更新日期:2017-11-10
  • Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-23
    Michio Miyajima, Baihao Zhang, Yuki Sugiura, Kazuhiro Sonomura, Matteo M Guerrini, Yumi Tsutsui, Mikako Maruya, Alexis Vogelzang, Kenji Chamoto, Kurara Honda, Takatoshi Hikida, Satomi Ito, Hongyan Qin, Rikako Sanuki, Keiichiro Suzuki, Takahisa Furukawa, Yasushi Ishihama, Fumihiko Matsuda, Makoto Suematsu, Tasuku Honjo, Sidonia Fagarasan

    Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior, Published online: 23 October 2017; doi:10.1038/ni.3867 NatureArticleSnippet(type=short-summary, markup= Fagarasan and colleagues show that excessive activation of T cells in mice deficient in the inhibitory receptor PD-1 causes a systemic decrease in tryptophan and tyrosine, which leads to deficiency in serotonin and dopamine in the brain and behavioral changes. , isJats=true)

    更新日期:2017-11-10
  • Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-23
    Svetlana A Fayngerts, Zhaojun Wang, Ali Zamani, Honghong Sun, Amanda E Boggs, Thomas P Porturas, Weidong Xie, Mei Lin, Terry Cathopoulis, Jason R Goldsmith, Anastassios Vourekas, Youhai H Chen

    Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2 Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2, Published online: 23 October 2017; doi:10.1038/ni.3866 NatureArticleSnippet(type=short-summary, markup= The polarization of leukocytes toward chemoattractants is essential for their directed migration. Chen and colleagues show that the phosphoinositide-transfer protein TIPE2 functions as a coordinator of leukocyte polarity. , isJats=true)

    更新日期:2017-11-10
  • Corrigendum: The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    Kalpana Manthiram, Qing Zhou, Ivona Aksentijevich, Daniel L Kastner

    Corrigendum: The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation Corrigendum: The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation, Published online: 18 October 2017; doi:10.1038/ni1117-1271a

    更新日期:2017-11-10
  • Erratum: Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    Eliana Mariño, James L Richards, Keiran H McLeod, Dragana Stanley, Yu Anne Yap, Jacinta Knight, Craig McKenzie, Jan Kranich, Ana Carolina Oliveira, Fernando J Rossello, Balasubramanian Krishnamurthy, Christian M Nefzger, Laurence Macia, Alison Thorburn, Alan G Baxter, Grant Morahan, Lee H Wong, Jose M Polo, Robert J Moore, Trevor J Lockett, Julie M Clarke, David L Topping, Leonard C Harrison, Charles R Mackay

    Erratum: Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes Erratum: Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes, Published online: 18 October 2017; doi:10.1038/ni1117-1271c

    更新日期:2017-11-10
  • FoxP3 partners up
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    David Bending, Masahiro Ono

    FoxP3 partners up FoxP3 partners up, Published online: 18 October 2017; doi:10.1038/ni.3852 NatureArticleSnippet(type=standfirst, markup= By switching its partners, FoxP3 segregates into functional and non-functional transcriptional complexes. , isJats=true)

    更新日期:2017-11-10
  • TFR cells trump autoimmune antibody responses to limit sedition
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    Michelle A Linterman, Kai-Michael Toellner

    TFR cells trump autoimmune antibody responses to limit sedition TFR cells trump autoimmune antibody responses to limit sedition, Published online: 18 October 2017; doi:10.1038/ni.3856 NatureArticleSnippet(type=standfirst, markup= The differentiation of follicular regulatory T cells can be limited by the cytokine IL-2, preventing the emergence of autoantibodies. This research identifies these cells as key regulators of the germinal center response. , isJats=true)

    更新日期:2017-11-10
  • CD28 enhances mitochondrial function
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    Laurie A. Dempsey

    CD28 enhances mitochondrial function CD28 enhances mitochondrial function, Published online: 18 October 2017; doi:10.1038/ni.3860

    更新日期:2017-11-10
  • Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-30
    Tomasz Maj, Wei Wang, Joel Crespo, Hongjuan Zhang, Weimin Wang, Shuang Wei, Lili Zhao, Linda Vatan, Irene Shao, Wojciech Szeliga, Costas Lyssiotis, J Rebecca Liu, Ilona Kryczek, Weiping Zou

    Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor, Published online: 30 October 2017; doi:10.1038/ni.3868 NatureArticleSnippet(type=short-summary, markup= The tumor microenvironment represents a stressful cellular environment. Zou and colleagues show that Treg cells in tumors have heightened sensitivity to apoptosis, but unexpectedly this increases their suppressive potency. , isJats=true)

    更新日期:2017-11-10
  • Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-23
    Michio Miyajima, Baihao Zhang, Yuki Sugiura, Kazuhiro Sonomura, Matteo M Guerrini, Yumi Tsutsui, Mikako Maruya, Alexis Vogelzang, Kenji Chamoto, Kurara Honda, Takatoshi Hikida, Satomi Ito, Hongyan Qin, Rikako Sanuki, Keiichiro Suzuki, Takahisa Furukawa, Yasushi Ishihama, Fumihiko Matsuda, Makoto Suematsu, Tasuku Honjo, Sidonia Fagarasan

    Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior, Published online: 23 October 2017; doi:10.1038/ni.3867 NatureArticleSnippet(type=short-summary, markup= Fagarasan and colleagues show that excessive activation of T cells in mice deficient in the inhibitory receptor PD-1 causes a systemic decrease in tryptophan and tyrosine, which leads to deficiency in serotonin and dopamine in the brain and behavioral changes. , isJats=true)

    更新日期:2017-11-10
  • Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-23
    Svetlana A Fayngerts, Zhaojun Wang, Ali Zamani, Honghong Sun, Amanda E Boggs, Thomas P Porturas, Weidong Xie, Mei Lin, Terry Cathopoulis, Jason R Goldsmith, Anastassios Vourekas, Youhai H Chen

    Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2 Direction of leukocyte polarization and migration by the phosphoinositide-transfer protein TIPE2, Published online: 23 October 2017; doi:10.1038/ni.3866 NatureArticleSnippet(type=short-summary, markup= The polarization of leukocytes toward chemoattractants is essential for their directed migration. Chen and colleagues show that the phosphoinositide-transfer protein TIPE2 functions as a coordinator of leukocyte polarity. , isJats=true)

    更新日期:2017-11-10
  • Corrigendum: The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    Kalpana Manthiram, Qing Zhou, Ivona Aksentijevich, Daniel L Kastner

    Corrigendum: The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation Corrigendum: The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation, Published online: 18 October 2017; doi:10.1038/ni1117-1271a

    更新日期:2017-11-10
  • Erratum: Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    Eliana Mariño, James L Richards, Keiran H McLeod, Dragana Stanley, Yu Anne Yap, Jacinta Knight, Craig McKenzie, Jan Kranich, Ana Carolina Oliveira, Fernando J Rossello, Balasubramanian Krishnamurthy, Christian M Nefzger, Laurence Macia, Alison Thorburn, Alan G Baxter, Grant Morahan, Lee H Wong, Jose M Polo, Robert J Moore, Trevor J Lockett, Julie M Clarke, David L Topping, Leonard C Harrison, Charles R Mackay

    Erratum: Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes Erratum: Gut microbial metabolites limit the frequency of autoimmune T cells and protect against type 1 diabetes, Published online: 18 October 2017; doi:10.1038/ni1117-1271c

    更新日期:2017-11-10
  • FoxP3 partners up
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    David Bending, Masahiro Ono

    FoxP3 partners up FoxP3 partners up, Published online: 18 October 2017; doi:10.1038/ni.3852 NatureArticleSnippet(type=standfirst, markup= By switching its partners, FoxP3 segregates into functional and non-functional transcriptional complexes. , isJats=true)

    更新日期:2017-11-10
  • TFR cells trump autoimmune antibody responses to limit sedition
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    Michelle A Linterman, Kai-Michael Toellner

    TFR cells trump autoimmune antibody responses to limit sedition TFR cells trump autoimmune antibody responses to limit sedition, Published online: 18 October 2017; doi:10.1038/ni.3856 NatureArticleSnippet(type=standfirst, markup= The differentiation of follicular regulatory T cells can be limited by the cytokine IL-2, preventing the emergence of autoantibodies. This research identifies these cells as key regulators of the germinal center response. , isJats=true)

    更新日期:2017-11-10
  • CD28 enhances mitochondrial function
    Nat. Immunol. (IF 21.506) Pub Date : 2017-10-18
    Laurie A. Dempsey

    CD28 enhances mitochondrial function CD28 enhances mitochondrial function, Published online: 18 October 2017; doi:10.1038/ni.3860

    更新日期:2017-11-10
  • Germline bias dictates cross-serotype reactivity in a common dengue-virus-specific CD8+ T cell response
    Nat. Immunol. (IF 21.506) Pub Date : 
    Abigail Culshaw, Kristin Ladell, Stephanie Gras, James E McLaren, Kelly L Miners, Carine Farenc, Heleen van den Heuvel, Emma Gostick, Wanwisa Dejnirattisai, Apirath Wangteeraprasert, Thaneeya Duangchinda, Pojchong Chotiyarnwong, Wannee Limpitikul, Sirijitt Vasanawathana, Prida Malasit, Tao Dong, Jamie Rossjohn, Juthathip Mongkolsapaya, David A Price, Gavin R Screaton

    Adaptive immune responses protect against infection with dengue virus (DENV), yet cross-reactivity with distinct serotypes can precipitate life-threatening clinical disease. We found that clonotypes expressing the T cell antigen receptor (TCR) β-chain variable region 11 (TRBV11-2) were 'preferentially' activated and mobilized within immunodominant human-leukocyte-antigen-(HLA)-A*11:01-restricted CD8+ T cell populations specific for variants of the nonstructural protein epitope NS3133 that characterize the serotypes DENV1, DENV3 and DENV4. In contrast, the NS3133-DENV2-specific repertoire was largely devoid of such TCRs. Structural analysis of a representative TRBV11-2+ TCR demonstrated that cross-serotype reactivity was governed by unique interplay between the variable antigenic determinant and germline-encoded residues in the second β-chain complementarity-determining region (CDR2β). Extensive mutagenesis studies of three distinct TRBV11-2+ TCRs further confirmed that antigen recognition was dependent on key contacts between the serotype-defined peptide and discrete residues in the CDR2β loop. Collectively, these data reveal an innate-like mode of epitope recognition with potential implications for the outcome of sequential exposure to heterologous DENVs.

    更新日期:2017-09-28
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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