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  • Corrigendum: NF-κB control of T cell development
    Nat. Immunol. (IF 21.506) Pub Date : 
    Steve Gerondakis, Thomas S Fulford, Nicole L Messina, Raelene J Grumont

    Corrigendum: NF-κB control of T cell developmentNature Immunology, Published online: 19 September 2017; doi:10.1038/ni1017-1173a

    更新日期:2017-09-21
  • Corrigendum: IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functions
    Nat. Immunol. (IF 21.506) Pub Date : 
    Chang-Han Lee, Gabrielle Romain, Wupeng Yan, Makiko Watanabe, Wissam Charab, Biliana Todorova, Jiwon Lee, Kendra Triplett, Moses Donkor, Oana I Lungu, Anja Lux, Nicholas Marshall, Margaret A Lindorfer, Odile Richard-Le Goff, Bianca Balbino, Tae Hyun Kang, Hidetaka Tanno, George Delidakis, Corrine Alford, Ronald P Taylor, Falk Nimmerjahn, Navin Varadarajan, Pierre Bruhns, Yan Jessie Zhang, George Georgiou

    Corrigendum: IgG Fc domains that bind C1q but not effector Fcγ receptors delineate the importance of complement-mediated effector functionsNature Immunology, Published online: 19 September 2017; doi:10.1038/ni1017-1173c

    更新日期:2017-09-21
  • Erratum: Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitors
    Nat. Immunol. (IF 21.506) Pub Date : 
    Jaeyop Lee, Yu Jerry Zhou, Wenji Ma, Wanwei Zhang, Arafat Aljoufi, Thomas Luh, Kimberly Lucero, Deguang Liang, Matthew Thomsen, Govind Bhagat, Yufeng Shen, Kang Liu

    Erratum: Lineage specification of human dendritic cells is marked by IRF8 expression in hematopoietic stem cells and multipotent progenitorsNature Immunology, Published online: 19 September 2017; doi:10.1038/ni1017-1173e

    更新日期:2017-09-21
  • IFN-λ 'guts' neutrophil-mediated inflammation
    Nat. Immunol. (IF 21.506) Pub Date : 
    Emily A Hemann, Johannes Schwerk, Ram Savan

    IFN-λ 'guts' neutrophil-mediated inflammationNature Immunology, Published online: 19 September 2017; doi:10.1038/ni.3834Interferon-λ (IFN-λ) curbs neutrophil-mediated intestinal inflammation by diminishing the production of reactive oxygen species and subsequent oxidative stress. This regulatory process is unique to IFN-λ and is independent of interferon-induced transcription and translation programs.

    更新日期:2017-09-21
  • B cell autoimmunity at the extremes
    Nat. Immunol. (IF 21.506) Pub Date : 
    Julie Zikherman, Clifford A Lowell

    B cell autoimmunity at the extremesNature Immunology, Published online: 19 September 2017; doi:10.1038/ni.3840Caveolin-1 has a critical role in orchestrating the membrane organization of B cells. In its absence, signaling via the B cell antigen receptor and B cell tolerance are impaired, which results in autoimmunity.

    更新日期:2017-09-21
  • Distinct Zika responses
    Nat. Immunol. (IF 21.506) Pub Date : 
    Laurie A. Dempsey

    Distinct Zika responsesNature Immunology, Published online: 19 September 2017; doi:10.1038/ni.3842

    更新日期:2017-09-21
  • CMTM6 controls PD-L1
    Nat. Immunol. (IF 21.506) Pub Date : 
    Ioana Visan

    CMTM6 controls PD-L1Nature Immunology, Published online: 19 September 2017; doi:10.1038/ni.3844

    更新日期:2017-09-21
  • Testicular macrophage origin
    Nat. Immunol. (IF 21.506) Pub Date : 
    Zoltan Fehervari

    Testicular macrophage originNature Immunology, Published online: 19 September 2017; doi:10.1038/ni.3846

    更新日期:2017-09-21
  • IFN-λ 'guts' neutrophil-mediated inflammation
    Nat. Immunol. (IF 21.506) Pub Date : 2017-09-19
    Emily A Hemann, Johannes Schwerk, Ram Savan

    Interferon-λ (IFN-λ) curbs neutrophil-mediated intestinal inflammation by diminishing the production of reactive oxygen species and subsequent oxidative stress. This regulatory process is unique to IFN-λ and is independent of interferon-induced transcription and translation programs.

    更新日期:2017-09-19
  • Disentangling the manifold functions of RORγt
    Nat. Immunol. (IF 21.506) Pub Date : 2017-09-19
    Thomas Korn

    A two-amino-acid substitution in the transcription factor RORγt disrupts its effect in establishing the transcriptional program of TH17 cells while leaving its function in the development of thymocytes and lymphoid-tissue–inducer cells largely intact.

    更新日期:2017-09-19
  • B cell autoimmunity at the extremes
    Nat. Immunol. (IF 21.506) Pub Date : 2017-09-19
    Julie Zikherman, Clifford A Lowell

    Caveolin-1 has a critical role in orchestrating the membrane organization of B cells. In its absence, signaling via the B cell antigen receptor and B cell tolerance are impaired, which results in autoimmunity.

    更新日期:2017-09-19
  • (T)Betting on innate lymphoid cells in CNS inflammatory disease
    Nat. Immunol. (IF 21.506) Pub Date : 2017-09-19
    Melissa A Brown, Abigail E Russi

    T-bet+NKp46+ subsets of group 1 and group 3 innate lymphoid cells within the meninges initiate neuroinflammation in central nervous system (CNS)-demyelinating disease by regulating both the stability of pathogenic T-bet+ T cells and their access to the CNS.

    更新日期:2017-09-19
  • Ontogeny and function of murine epidermal Langerhans cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-09-19
    Daniel H Kaplan

    Langerhans cells (LCs) are epidermis-resident antigen-presenting cells that share a common ontogeny with macrophages but function as dendritic cells (DCs). Their development, recruitment and retention in the epidermis is orchestrated by interactions with keratinocytes through multiple mechanisms. LC and dermal DC subsets often show functional redundancy, but LCs are required for specific types of adaptive immune responses when antigen is concentrated in the epidermis. This Review will focus on those developmental and functional properties that are unique to LCs.

    更新日期:2017-09-19
  • IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-28
    Achille Broggi, Yunhao Tan, Francesca Granucci, Ivan Zanoni

    Interferon-λ (IFN-λ) is a central regulator of mucosal immunity; however, its signaling specificity relative to that of type I interferons is poorly defined. IFN-λ can induce antiviral interferon-stimulated genes (ISGs) in epithelia, while the effect of IFN-λ in non-epithelial cells remains unclear. Here we report that neutrophils responded to IFN-λ. We found that in addition to inducing ISG transcription, IFN-λ (but not IFN-β) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils. In mice, IFN-λ was elicited by enteric viruses and acted on neutrophils to decrease oxidative stress and intestinal damage. Thus, IFN-λ acted as a unique immunomodulatory agent by modifying transcriptional and non-translational neutrophil responses, which might permit a controlled development of the inflammatory process.

    更新日期:2017-09-19
  • The immunology of the allergy epidemic and the hygiene hypothesis
    Nat. Immunol. (IF 21.506) Pub Date : 2017-09-19
    Bart N Lambrecht, Hamida Hammad

    Lambrecht and Hammad discuss how microbial diversity or dysbiosis influences epithelial barrier tissues and the impact of such interactions on the development of allergic disease.

    更新日期:2017-09-19
  • The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-28
    Qingliang Zheng, Jin Hou, Ye Zhou, Zhenyang Li, Xuetao Cao

    DEAD-box (DDX) helicases are vital for the recognition of RNA and metabolism and are critical for the initiation of antiviral innate immunity. Modification of RNA is involved in many biological processes; however, its role in antiviral innate immunity has remained unclear. Here we found that nuclear DDX member DDX46 inhibited the production of type I interferons after viral infection. DDX46 bound Mavs, Traf3 and Traf6 transcripts (which encode signaling molecules involved in antiviral responses) via their conserved CCGGUU element. After viral infection, DDX46 recruited ALKBH5, an 'eraser' of the RNA modification N6-methyladenosine (m6A), via DDX46's DEAD helicase domain to demethylate those m6A-modified antiviral transcripts. It consequently enforced their retention in the nucleus and therefore prevented their translation and inhibited interferon production. DDX46 also suppressed antiviral innate immunity in vivo. Thus, DDX46 inhibits antiviral innate responses by entrapping selected antiviral transcripts in the nucleus by erasing their m6A modification, a modification normally required for export from the nucleus and translation.

    更新日期:2017-09-19
  • Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-21
    Sung Ho Park, Kyuho Kang, Eugenia Giannopoulou, Yu Qiao, Keunsoo Kang, Geonho Kim, Kyung-Hyun Park-Min, Lionel B Ivashkiv

    Cross-regulation of Toll-like receptor (TLR) responses by cytokines is essential for effective host defense, avoidance of toxicity and homeostasis, but the underlying mechanisms are not well understood. Our comprehensive epigenomics approach to the analysis of human macrophages showed that the proinflammatory cytokines TNF and type I interferons induced transcriptional cascades that altered chromatin states to broadly reprogram responses induced by TLR4. TNF tolerized genes encoding inflammatory molecules to prevent toxicity while preserving the induction of genes encoding antiviral and metabolic molecules. Type I interferons potentiated the inflammatory function of TNF by priming chromatin to prevent the silencing of target genes of the transcription factor NF-κB that encode inflammatory molecules. The priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between interferons and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify previously unknown functions and mechanisms of action of these cytokines.

    更新日期:2017-09-19
  • T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-14
    Brandon Kwong, Rejane Rua, Yuanyuan Gao, John Flickinger, Yan Wang, Michael J Kruhlak, Jinfang Zhu, Eric Vivier, Dorian B McGavern, Vanja Lazarevic

    The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46+ innate lymphoid cells (ILCs) in the initiation of CD4+ TH17-mediated neuroinflammation. Loss of T-bet specifically in NKp46+ ILCs profoundly impaired the ability of myelin-reactive TH17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46+ ILCs localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of proinflammatory cytokines, chemokines and matrix metalloproteinases, which together facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46+ ILCs in the development of CNS autoimmune disease.

    更新日期:2017-09-19
  • A two-amino-acid substitution in the transcription factor RORγt disrupts its function in TH17 differentiation but not in thymocyte development
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-28
    Zhiheng He, Jian Ma, Ruiqing Wang, Jing Zhang, Zhaofeng Huang, Fei Wang, Subha Sen, Ellen V Rothenberg, Zuoming Sun

    The transcription factor RORγt regulates differentiation of the TH17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORγt prevents TH17 cell–mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in RORγt (RORγtM) that 'preferentially' disrupted TH17 differentiation but not thymocyte development. Mice expressing RORγtM were resistant to EAE associated with defective TH17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. RORγtM showed less ubiquitination at Lys69 that was selectively required for TH17 differentiation but not T cell development. This study will inform the development of treatments that selectively target TH17 cell–mediated autoimmunity but do not affect thymocyte development or induce lymphoma.

    更新日期:2017-09-19
  • Asynchronous lineage priming determines commitment to T cell and B cell lineages in fetal liver
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-21
    Claire Berthault, Cyrille Ramond, Odile Burlen-Defranoux, Guillaume Soubigou, Sylvestre Chea, Rachel Golub, Pablo Pereira, Paulo Vieira, Ana Cumano

    The molecular events that initiate lymphoid-lineage specification remain unidentified because the stages of differentiation during which lineage commitment occurs are difficult to characterize. We isolated fetal liver progenitor cells undergoing restriction of their differentiation potential toward the T cell–innate lymphoid cell lineage or the B cell lineage. Transcripts that defined the molecular signatures of these two subsets were sequentially upregulated in lympho-myeloid precursor cells and in common lymphoid progenitor cells, respectively, and this preceded lineage restriction; this indicates that T cell–versus–B cell commitment is not a binary fate 'decision'. The T cell–bias and B cell–bias transcriptional programs were frequently co-expressed in common lymphoid progenitor cells and were segregated in subsets biased toward T cell differentiation or B cell differentiation, after interleukin 7 (IL-7) signaling that controlled the number of progenitor cells engaging in T cell differentiation versus B cell differentiation.

    更新日期:2017-09-19
  • Caveolin-1-dependent nanoscale organization of the BCR regulates B cell tolerance
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-14
    Susana Minguet, Kathrin Kläsener, Anna-Maria Schaffer, Gina J Fiala, Teresa Osteso-Ibánez, Katrin Raute, Inmaculada Navarro-Lérida, Frederike A Hartl, Maximilian Seidl, Michael Reth, Miguel A Del Pozo

    Caveolin-1 (Cav1) regulates the nanoscale organization and compartmentalization of the plasma membrane. Here we found that Cav1 controlled the distribution of nanoclusters of isotype-specific B cell antigen receptors (BCRs) on the surface of B cells. In mature B cells stimulated with antigen, the immunoglobulin M BCR (IgM-BCR) gained access to lipid domains enriched for GM1 glycolipids, by a process that was dependent on the phosphorylation of Cav1 by the Src family of kinases. Antigen-induced reorganization of nanoclusters of IgM-BCRs and IgD-BCRs regulated BCR signaling in vivo. In immature Cav1-deficient B cells, altered nanoscale organization of IgM-BCRs resulted in a failure of receptor editing and a skewed repertoire of B cells expressing immunoglobulin-μ heavy chains with hallmarks of poly- and auto-reactivity, which ultimately led to autoimmunity in mice. Thus, Cav1 emerges as a cell-intrinsic regulator that prevents B cell–induced autoimmunity by means of its role in plasma-membrane organization.

    更新日期:2017-09-19
  • Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-07
    Michael Delacher, Charles D Imbusch, Dieter Weichenhan, Achim Breiling, Agnes Hotz-Wagenblatt, Ulrike Träger, Ann-Cathrin Hofer, Danny Kägebein, Qi Wang, Felix Frauhammer, Jan-Philipp Mallm, Katharina Bauer, Carl Herrmann, Philipp A Lang, Benedikt Brors, Christoph Plass, Markus Feuerer

    Regulatory T cells (Treg cells) perform two distinct functions: they maintain self-tolerance, and they support organ homeostasis by differentiating into specialized tissue Treg cells. We found that epigenetic modifications defined the molecular characteristics of tissue Treg cells. Tagmentation-based whole-genome bisulfite sequencing revealed more than 11,000 regions that were methylated differentially in pairwise comparisons of tissue Treg cell populations and lymphoid T cells. Similarities in the epigenetic landscape led to the identification of a common tissue Treg cell population that was present in many organs and was characterized by gain and loss of DNA methylation that included many gene sites associated with the TH2 subset of helper T cells, such as the gene encoding cytokine IL-33 receptor ST2, as well as the production of tissue-regenerative factors. Furthermore, the ST2-expressing population was dependent on the transcriptional regulator BATF and could be expanded by IL-33. Thus, tissue Treg cells integrate multiple waves of epigenetic reprogramming that define their tissue-restricted specialization.

    更新日期:2017-09-19
  • Srebp-controlled glucose metabolism is essential for NK cell functional responses
    Nat. Immunol. (IF 21.506) Pub Date : 2017-09-18
    Nadine Assmann, Katie L O'Brien, Raymond P Donnelly, Lydia Dyck, Vanessa Zaiatz-Bittencourt, Róisín M Loftus, Paul Heinrich, Peter J Oefner, Lydia Lynch, Clair M Gardiner, Katja Dettmer, David K Finlay

    Activated natural killer (NK) cells engage in a robust metabolic response that is required for normal effector function. Using genetic, pharmacological and metabolic analyses, we demonstrated an essential role for Srebp transcription factors in cytokine-induced metabolic reprogramming of NK cells that was independent of their conventional role in the control of lipid synthesis. Srebp was required for elevated glycolysis and oxidative phosphorylation and promoted a distinct metabolic pathway configuration in which glucose was metabolized to cytosolic citrate via the citrate–malate shuttle. Preventing the activation of Srebp or direct inhibition of the citrate–malate shuttle inhibited production of interferon-γ and NK cell cytotoxicity. Thus, Srebp controls glucose metabolism in NK cells, and this Srebp-dependent regulation is critical for NK cell effector function.

    更新日期:2017-09-18
  • Dynamic regulation of T follicular regulatory cell responses by interleukin 2 during influenza infection
    Nat. Immunol. (IF 21.506) Pub Date : 
    Davide Botta, Michael J Fuller, Tatiana T Marquez-Lago, Holly Bachus, John E Bradley, Amy S Weinmann, Allan J Zajac, Troy D Randall, Frances E Lund, Beatriz León, André Ballesteros-Tato

    Interleukin 2 (IL-2) promotes Foxp3+ regulatory T (Treg) cell responses, but inhibits T follicular helper (TFH) cell development. However, it is not clear how IL-2 affects T follicular regulatory (TFR) cells, a cell type with properties of both Treg and TFH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented TFR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some Treg cells downregulated CD25, upregulated Bcl-6 and differentiated into TFR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones. Thus, unlike its effects on conventional Treg cells, IL-2 inhibits TFR cell responses.

    更新日期:2017-09-12
  • De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors
    Nat. Immunol. (IF 21.506) Pub Date : 
    Anna Johansson-Percival, Bo He, Zhi-Jie Li, Alva Kjellén, Karen Russell, Ji Li, Irma Larma, Ruth Ganss

    The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.

    更新日期:2017-09-12
  • Different molecular complexes that mediate transcriptional induction and repression by FoxP3
    Nat. Immunol. (IF 21.506) Pub Date : 
    Ho-Keun Kwon, Hui-Min Chen, Diane Mathis, Christophe Benoist

    FoxP3 conditions the transcriptional signature and functional facets of regulatory T cells (Treg cells). Its mechanism of action, whether as an activator or a repressor, has remained unclear. Here, chromatin analysis showed that FoxP3 bound active enhancer elements, not repressed chromatin, around loci over- or under-expressed in Treg cells. We evaluated the impact of a panel of FoxP3 mutants on its transcriptional activity and interactions with DNA, transcriptional cofactors and chromatin. Computational integration, confirmed by biochemical interaction and size analyses, showed that FoxP3 existed in distinct multimolecular complexes. It was active and primarily an activator when complexed with the transcriptional factors RELA, IKZF2 and KAT5. In contrast, FoxP3 was inactive when complexed with the histone methyltransferase EZH2 and transcription factors YY1 and IKZF3. The latter complex partitioned to a peripheral region of the nucleus, as shown by super-resolution microscopy. Thus, FoxP3 acts in multimodal fashion to directly activate or repress transcription, in a context- and partner-dependent manner, to govern Treg cell phenotypes.

    更新日期:2017-09-12
  • The RNA helicase DDX46 inhibits innate immunity by entrapping m6A-demethylated antiviral transcripts in the nucleus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-28
    Qingliang Zheng, Jin Hou, Ye Zhou, Zhenyang Li, Xuetao Cao

    DEAD-box (DDX) helicases are vital for the recognition of RNA and metabolism and are critical for the initiation of antiviral innate immunity. Modification of RNA is involved in many biological processes; however, its role in antiviral innate immunity has remained unclear. Here we found that nuclear DDX member DDX46 inhibited the production of type I interferons after viral infection. DDX46 bound Mavs, Traf3 and Traf6 transcripts (which encode signaling molecules involved in antiviral responses) via their conserved CCGGUU element. After viral infection, DDX46 recruited ALKBH5, an 'eraser' of the RNA modification N6-methyladenosine (m6A), via DDX46's DEAD helicase domain to demethylate those m6A-modified antiviral transcripts. It consequently enforced their retention in the nucleus and therefore prevented their translation and inhibited interferon production. DDX46 also suppressed antiviral innate immunity in vivo. Thus, DDX46 inhibits antiviral innate responses by entrapping selected antiviral transcripts in the nucleus by erasing their m6A modification, a modification normally required for export from the nucleus and translation.

    更新日期:2017-09-07
  • A two-amino-acid substitution in the transcription factor RORγt disrupts its function in TH17 differentiation but not in thymocyte development
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-28
    Zhiheng He, Jian Ma, Ruiqing Wang, Jing Zhang, Zhaofeng Huang, Fei Wang, Subha Sen, Ellen V Rothenberg, Zuoming Sun

    The transcription factor RORγt regulates differentiation of the TH17 subset of helper T cells, thymic T cell development and lymph-node genesis. Although elimination of RORγt prevents TH17 cell–mediated experimental autoimmune encephalomyelitis (EAE), it also disrupts thymocyte development, which could lead to lethal thymic lymphoma. Here we identified a two-amino-acid substitution in RORγt (RORγtM) that 'preferentially' disrupted TH17 differentiation but not thymocyte development. Mice expressing RORγtM were resistant to EAE associated with defective TH17 differentiation but maintained normal thymocyte development and normal lymph-node genesis, except for Peyer's patches. RORγtM showed less ubiquitination at Lys69 that was selectively required for TH17 differentiation but not T cell development. This study will inform the development of treatments that selectively target TH17 cell–mediated autoimmunity but do not affect thymocyte development or induce lymphoma.

    更新日期:2017-09-07
  • IFN-λ suppresses intestinal inflammation by non-translational regulation of neutrophil function
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-28
    Achille Broggi, Yunhao Tan, Francesca Granucci, Ivan Zanoni

    Interferon-λ (IFN-λ) is a central regulator of mucosal immunity; however, its signaling specificity relative to that of type I interferons is poorly defined. IFN-λ can induce antiviral interferon-stimulated genes (ISGs) in epithelia, while the effect of IFN-λ in non-epithelial cells remains unclear. Here we report that neutrophils responded to IFN-λ. We found that in addition to inducing ISG transcription, IFN-λ (but not IFN-β) specifically activated a translation-independent signaling pathway that diminished the production of reactive oxygen species and degranulation in neutrophils. In mice, IFN-λ was elicited by enteric viruses and acted on neutrophils to decrease oxidative stress and intestinal damage. Thus, IFN-λ acted as a unique immunomodulatory agent by modifying transcriptional and non-translational neutrophil responses, which might permit a controlled development of the inflammatory process.

    更新日期:2017-09-07
  • Pathways in opposition
    Nat. Immunol. (IF 21.506) Pub Date : 
    Zoltan Fehervari

    Pathways in opposition Nature Immunology, Published online: 22 August 2017; doi:10.1038/ni.3822

    更新日期:2017-09-07
  • Rodent hepatitis C model
    Nat. Immunol. (IF 21.506) Pub Date : 
    Laurie A. Dempsey

    Rodent hepatitis C model Nature Immunology, Published online: 22 August 2017; doi:10.1038/ni.3824

    更新日期:2017-09-07
  • Losing IFN
    Nat. Immunol. (IF 21.506) Pub Date : 
    Ioana Visan

    Losing IFN Nature Immunology, Published online: 22 August 2017; doi:10.1038/ni.3826

    更新日期:2017-09-07
  • Gene regulation in the immune system by long noncoding RNAs
    Nat. Immunol. (IF 21.506) Pub Date : 
    Y Grace Chen, Ansuman T Satpathy, Howard Y Chang

    Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression in the immune system. Studies have shown that lncRNAs are expressed in a highly lineage-specific manner and control the differentiation and function of innate and adaptive cell types. In this Review, we focus on mechanisms used by lncRNAs to regulate genes encoding products involved in the immune response, including direct interactions with chromatin, RNA and proteins. In addition, we address new areas of lncRNA biology, such as the functions of enhancer RNAs, circular RNAs and chemical modifications to RNA in cellular processes. We emphasize critical gaps in knowledge and future prospects for the roles of lncRNAs in the immune system and autoimmune disease.

    更新日期:2017-09-07
  • MLL4 keeps Foxp3 in the loop
    Nat. Immunol. (IF 21.506) Pub Date : 
    Dong-Mei Zhao, Hai-Hui Xue

    MLL4 keeps Foxp3 in the loop Nature Immunology, Published online: 22 August 2017; doi:10.1038/ni.3811 The histone lysine methyltransferase MLL4 primes the locus encoding the transcription factor Foxp3 for transcriptional activation in thymus-derived and inducible regulatory T cells.

    更新日期:2017-09-07
  • Asynchronous lineage priming determines commitment to T cell and B cell lineages in fetal liver
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-21
    Claire Berthault, Cyrille Ramond, Odile Burlen-Defranoux, Guillaume Soubigou, Sylvestre Chea, Rachel Golub, Pablo Pereira, Paulo Vieira, Ana Cumano

    The molecular events that initiate lymphoid-lineage specification remain unidentified because the stages of differentiation during which lineage commitment occurs are difficult to characterize. We isolated fetal liver progenitor cells undergoing restriction of their differentiation potential toward the T cell–innate lymphoid cell lineage or the B cell lineage. Transcripts that defined the molecular signatures of these two subsets were sequentially upregulated in lympho-myeloid precursor cells and in common lymphoid progenitor cells, respectively, and this preceded lineage restriction; this indicates that T cell–versus–B cell commitment is not a binary fate 'decision'. The T cell–bias and B cell–bias transcriptional programs were frequently co-expressed in common lymphoid progenitor cells and were segregated in subsets biased toward T cell differentiation or B cell differentiation, after interleukin 7 (IL-7) signaling that controlled the number of progenitor cells engaging in T cell differentiation versus B cell differentiation.

    更新日期:2017-09-06
  • Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-21
    Sung Ho Park, Kyuho Kang, Eugenia Giannopoulou, Yu Qiao, Keunsoo Kang, Geonho Kim, Kyung-Hyun Park-Min, Lionel B Ivashkiv

    Cross-regulation of Toll-like receptor (TLR) responses by cytokines is essential for effective host defense, avoidance of toxicity and homeostasis, but the underlying mechanisms are not well understood. Our comprehensive epigenomics approach to the analysis of human macrophages showed that the proinflammatory cytokines TNF and type I interferons induced transcriptional cascades that altered chromatin states to broadly reprogram responses induced by TLR4. TNF tolerized genes encoding inflammatory molecules to prevent toxicity while preserving the induction of genes encoding antiviral and metabolic molecules. Type I interferons potentiated the inflammatory function of TNF by priming chromatin to prevent the silencing of target genes of the transcription factor NF-κB that encode inflammatory molecules. The priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between interferons and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify previously unknown functions and mechanisms of action of these cytokines.

    更新日期:2017-09-06
  • T-bet-dependent NKp46+ innate lymphoid cells regulate the onset of TH17-induced neuroinflammation
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-14
    Brandon Kwong, Rejane Rua, Yuanyuan Gao, John Flickinger, Yan Wang, Michael J Kruhlak, Jinfang Zhu, Eric Vivier, Dorian B McGavern, Vanja Lazarevic

    The transcription factor T-bet has been associated with increased susceptibility to systemic and organ-specific autoimmunity, but the mechanism by which T-bet expression promotes neuroinflammation remains unknown. In this study, we demonstrate a cardinal role of T-bet-dependent NKp46+ innate lymphoid cells (ILCs) in the initiation of CD4+ TH17-mediated neuroinflammation. Loss of T-bet specifically in NKp46+ ILCs profoundly impaired the ability of myelin-reactive TH17 cells to invade central nervous system (CNS) tissue and protected the mice from autoimmunity. T-bet-dependent NKp46+ ILCs localized in the meninges and acted as chief coordinators of meningeal inflammation by inducing the expression of proinflammatory cytokines, chemokines and matrix metalloproteinases, which together facilitated T cell entry into CNS parenchyma. Our findings uncover a detrimental role of T-bet-dependent NKp46+ ILCs in the development of CNS autoimmune disease.

    更新日期:2017-09-06
  • Caveolin-1-dependent nanoscale organization of the BCR regulates B cell tolerance
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-14
    Susana Minguet, Kathrin Kläsener, Anna-Maria Schaffer, Gina J Fiala, Teresa Osteso-Ibánez, Katrin Raute, Inmaculada Navarro-Lérida, Frederike A Hartl, Maximilian Seidl, Michael Reth, Miguel A Del Pozo

    Caveolin-1 (Cav1) regulates the nanoscale organization and compartmentalization of the plasma membrane. Here we found that Cav1 controlled the distribution of nanoclusters of isotype-specific B cell antigen receptors (BCRs) on the surface of B cells. In mature B cells stimulated with antigen, the immunoglobulin M BCR (IgM-BCR) gained access to lipid domains enriched for GM1 glycolipids, by a process that was dependent on the phosphorylation of Cav1 by the Src family of kinases. Antigen-induced reorganization of nanoclusters of IgM-BCRs and IgD-BCRs regulated BCR signaling in vivo. In immature Cav1-deficient B cells, altered nanoscale organization of IgM-BCRs resulted in a failure of receptor editing and a skewed repertoire of B cells expressing immunoglobulin-μ heavy chains with hallmarks of poly- and auto-reactivity, which ultimately led to autoimmunity in mice. Thus, Cav1 emerges as a cell-intrinsic regulator that prevents B cell–induced autoimmunity by means of its role in plasma-membrane organization.

    更新日期:2017-09-06
  • SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-31
    Victor S Cortez, Tyler K Ulland, Luisa Cervantes-Barragan, Jennifer K Bando, Michelle L Robinette, Qianli Wang, Andrew J White, Susan Gilfillan, Marina Cella, Marco Colonna

    Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-β family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGFβR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells.

    更新日期:2017-09-06
  • Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-31
    Yulong Gao, Fernando Souza-Fonseca-Guimaraes, Tobias Bald, Susanna S Ng, Arabella Young, Shin Foong Ngiow, Jai Rautela, Jasmin Straube, Nic Waddell, Stephen J Blake, Juming Yan, Laurent Bartholin, Jason S Lee, Eric Vivier, Kazuyoshi Takeda, Meriem Messaoudene, Laurence Zitvogel, Michele W L Teng, Gabrielle T Belz, Christian R Engwerda, Nicholas D Huntington, Kyohei Nakamura, Michael Hölzel, Mark J Smyth

    Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-β-signaling-dependent conversion of NK cells (CD49a−CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b−Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-β-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.

    更新日期:2017-09-06
  • MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-31
    Katarzyna Placek, Gangqing Hu, Kairong Cui, Dunfang Zhang, Yi Ding, Ji-Eun Lee, Younghoon Jang, Chaochen Wang, Joanne Elizabeth Konkel, Jiuzhou Song, Chengyu Liu, Kai Ge, Wanjun Chen, Keji Zhao

    MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (Treg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4-binding site diminished the abundance of H3K4me1 at the regulatory elements of the gene encoding the transcription factor Foxp3 that were looped to the MLL4-binding site and compromised both the thymic differentiation and the inducible differentiation of Treg cells. We found that MLL4 catalyzed methylation of H3K4 at distant unbound enhancers via chromatin looping, which identifies a previously unknown mechanism for regulating the T cell enhancer landscape and affecting Treg cell differentiation.

    更新日期:2017-09-06
  • Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-24
    Yi Shen, Zhenke Wen, Yinyin Li, Eric L Matteson, Jison Hong, Jörg J Goronzy, Cornelia M Weyand

    Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells—specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. ATPlopyruvatelo conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoration of pyruvate production or inhibition of fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their proarthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites.

    更新日期:2017-09-06
  • α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-17

    Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of α-ketoglutarate (αKG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high αKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, αKG contributes to endotoxin tolerance after M1 activation. This study reveals new mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming.

    更新日期:2017-09-06
  • Increased cathepsin S in Prdm1−/− dendritic cells alters the TFH cell repertoire and contributes to lupus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-10

    Aberrant population expansion of follicular helper T cells (TFH cells) occurs in patients with lupus. An unanswered question is whether an altered repertoire of T cell antigen receptors (TCRs) is associated with such expansion. Here we found that the transcription factor Blimp-1 (encoded by Prdm1) repressed expression of the gene encoding cathepsin S (Ctss), a cysteine protease that cleaves invariant chains and produces antigenic peptides for loading onto major histocompatibility complex (MHC) class II molecules. The increased CTSS expression in dendritic cells (DCs) from female mice with dendritic cell–specific conditional knockout of Prdm1 (CKO mice) altered the presentation of antigen to CD4+ T cells. Analysis of complementarity-determining region 3 (CDR3) regions containing the β-chain variable region (Vβ) demonstrated a more diverse repertoire of TFH cells from female CKO mice than of those from wild-type mice. In vivo treatment of CKO mice with a CTSS inhibitor abolished the lupus-related phenotype and reduced the diversity of the TFH cell TCR repertoire. Thus, Blimp-1 deficiency in DCs led to loss of appropriate regulation of Ctss expression in female mice and thereby modulated antigen presentation and the TFH cell repertoire to contribute to autoimmunity.

    更新日期:2017-09-06
  • Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-03
    Masashi Kanayama, Shengjie Xu, Keiko Danzaki, Jason R Gibson, Makoto Inoue, Simon G Gregory, Mari L Shinohara

    The balance of myeloid populations and lymphoid populations must be well controlled. Here we found that osteopontin (OPN) skewed this balance during pathogenic conditions such as infection and autoimmunity. Notably, two isoforms of OPN exerted distinct effects in shifting this balance through cell-type-specific regulation of apoptosis. Intracellular OPN (iOPN) diminished the population size of myeloid progenitor cells and myeloid cells, and secreted OPN (sOPN) increase the population size of lymphoid cells. The total effect of OPN on skewing the leukocyte population balance was observed as host sensitivity to early systemic infection with Candida albicans and T cell–mediated colitis. Our study suggests previously unknown detrimental roles for two OPN isoforms in causing the imbalance of leukocyte populations.

    更新日期:2017-09-06
  • Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-07
    Michael Delacher, Charles D Imbusch, Dieter Weichenhan, Achim Breiling, Agnes Hotz-Wagenblatt, Ulrike Träger, Ann-Cathrin Hofer, Danny Kägebein, Qi Wang, Felix Frauhammer, Jan-Philipp Mallm, Katharina Bauer, Carl Herrmann, Philipp A Lang, Benedikt Brors, Christoph Plass, Markus Feuerer

    Regulatory T cells (Treg cells) perform two distinct functions: they maintain self-tolerance, and they support organ homeostasis by differentiating into specialized tissue Treg cells. We found that epigenetic modifications defined the molecular characteristics of tissue Treg cells. Tagmentation-based whole-genome bisulfite sequencing revealed more than 11,000 regions that were methylated differentially in pairwise comparisons of tissue Treg cell populations and lymphoid T cells. Similarities in the epigenetic landscape led to the identification of a common tissue Treg cell population that was present in many organs and was characterized by gain and loss of DNA methylation that included many gene sites associated with the TH2 subset of helper T cells, such as the gene encoding cytokine IL-33 receptor ST2, as well as the production of tissue-regenerative factors. Furthermore, the ST2-expressing population was dependent on the transcriptional regulator BATF and could be expanded by IL-33. Thus, tissue Treg cells integrate multiple waves of epigenetic reprogramming that define their tissue-restricted specialization.

    更新日期:2017-09-06
  • Translation is actively regulated during the differentiation of CD8+ effector T cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-17

    T cells undergo myriad changes after antigenic activation. Araki and colleagues show that CD8+ T cells exert dynamic control of mRNA translation during differentiation into effector and memory cells.

    更新日期:2017-09-06
  • Myelopoiesis embraces its inner weakness
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-22
    Motti Gerlic, Ben A Croker

    The ability to expand and contract populations of myeloid and lymphoid cells during emergency hematopoiesis helps shape the immune response. The expression of intracellular and soluble forms of osteopontin regulates apoptosis thresholds differently in myeloid cells and lymphoid cells to counter infection.

    更新日期:2017-08-22
  • NK cells join the plasticity party
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-22
    Jonathan S Silver, Alison A Humbles

    The cytokine TGF-β allows tumors to evade the immune system by converting conventional natural killer cells into type 1 innate lymphoid cells devoid of cytotoxic function.

    更新日期:2017-08-22
  • MLL4 keeps Foxp3 in the loop
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-22
    Dong-Mei Zhao, Hai-Hui Xue

    The histone lysine methyltransferase MLL4 primes the locus encoding the transcription factor Foxp3 for transcriptional activation in thymus-derived and inducible regulatory T cells.

    更新日期:2017-08-22
  • Fat T cells go to the joint
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-22
    George C Tsokos

    Poor glycolysis and increased fatty-acid synthesis feed the locomotion machinery in T cells from people with rheumatoid arthritis and allow these cells to enter the synovium and propagate joint inflammation and destruction.

    更新日期:2017-08-22
  • Gene regulation in the immune system by long noncoding RNAs
    Nat. Immunol. (IF 21.506) Pub Date : 2017-08-22
    Y Grace Chen, Ansuman T Satpathy, Howard Y Chang

    Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression in the immune system. Studies have shown that lncRNAs are expressed in a highly lineage-specific manner and control the differentiation and function of innate and adaptive cell types. In this Review, we focus on mechanisms used by lncRNAs to regulate genes encoding products involved in the immune response, including direct interactions with chromatin, RNA and proteins. In addition, we address new areas of lncRNA biology, such as the functions of enhancer RNAs, circular RNAs and chemical modifications to RNA in cellular processes. We emphasize critical gaps in knowledge and future prospects for the roles of lncRNAs in the immune system and autoimmune disease.

    更新日期:2017-08-22
  • Skewing of the population balance of lymphoid and myeloid cells by secreted and intracellular osteopontin
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-03
    Masashi Kanayama, Shengjie Xu, Keiko Danzaki, Jason R Gibson, Makoto Inoue, Simon G Gregory, Mari L Shinohara

    The balance of myeloid populations and lymphoid populations must be well controlled. Here we found that osteopontin (OPN) skewed this balance during pathogenic conditions such as infection and autoimmunity. Notably, two isoforms of OPN exerted distinct effects in shifting this balance through cell-type-specific regulation of apoptosis. Intracellular OPN (iOPN) diminished the population size of myeloid progenitor cells and myeloid cells, and secreted OPN (sOPN) increase the population size of lymphoid cells. The total effect of OPN on skewing the leukocyte population balance was observed as host sensitivity to early systemic infection with Candida albicans and T cell–mediated colitis. Our study suggests previously unknown detrimental roles for two OPN isoforms in causing the imbalance of leukocyte populations.

    更新日期:2017-08-22
  • α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-17
    Pu-Ste Liu, Haiping Wang, Xiaoyun Li, Tung Chao, Tony Teav, Stefan Christen, Giusy Di Conza, Wan-Chen Cheng, Chih-Hung Chou, Magdalena Vavakova, Charlotte Muret, Koen Debackere, Massimiliano Mazzone, Hsien-Da Huang, Sarah-Maria Fendt, Julijana Ivanisevic, Ping-Chih Ho

    Glutamine metabolism provides synergistic support for macrophage activation and elicitation of desirable immune responses; however, the underlying mechanisms regulated by glutamine metabolism to orchestrate macrophage activation remain unclear. Here we show that the production of α-ketoglutarate (αKG) via glutaminolysis is important for alternative (M2) activation of macrophages, including engagement of fatty acid oxidation (FAO) and Jmjd3-dependent epigenetic reprogramming of M2 genes. This M2-promoting mechanism is further modulated by a high αKG/succinate ratio, whereas a low ratio strengthens the proinflammatory phenotype in classically activated (M1) macrophages. As such, αKG contributes to endotoxin tolerance after M1 activation. This study reveals new mechanistic regulations by which glutamine metabolism tailors the immune responses of macrophages through metabolic and epigenetic reprogramming.

    更新日期:2017-08-22
  • SMAD4 impedes the conversion of NK cells into ILC1-like cells by curtailing non-canonical TGF-β signaling
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-31
    Victor S Cortez, Tyler K Ulland, Luisa Cervantes-Barragan, Jennifer K Bando, Michelle L Robinette, Qianli Wang, Andrew J White, Susan Gilfillan, Marina Cella, Marco Colonna

    Among the features that distinguish type 1 innate lymphoid cells (ILC1s) from natural killer (NK) cells is a gene signature indicative of 'imprinting' by cytokines of the TGF-β family. We studied mice in which ILC1s and NK cells lacked SMAD4, a signal transducer that facilitates the canonical signaling pathway common to all cytokines of the TGF-β family. While SMAD4 deficiency did not affect ILC1 differentiation, NK cells unexpectedly acquired an ILC1-like gene signature and were unable to control tumor metastasis or viral infection. Mechanistically, SMAD4 restrained non-canonical TGF-β signaling mediated by the cytokine receptor TGFβR1 in NK cells. NK cells from a SMAD4-deficient person affected by polyposis were also hyper-responsive to TGF-β. These results identify SMAD4 as a previously unknown regulator that restricts non-canonical TGF-β signaling in NK cells.

    更新日期:2017-08-22
  • Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-31
    Yulong Gao, Fernando Souza-Fonseca-Guimaraes, Tobias Bald, Susanna S Ng, Arabella Young, Shin Foong Ngiow, Jai Rautela, Jasmin Straube, Nic Waddell, Stephen J Blake, Juming Yan, Laurent Bartholin, Jason S Lee, Eric Vivier, Kazuyoshi Takeda, Meriem Messaoudene, Laurence Zitvogel, Michele W L Teng, Gabrielle T Belz, Christian R Engwerda, Nicholas D Huntington, Kyohei Nakamura, Michael Hölzel, Mark J Smyth

    Avoiding destruction by immune cells is a hallmark of cancer, yet how tumors ultimately evade control by natural killer (NK) cells remains incompletely defined. Using global transcriptomic and flow-cytometry analyses and genetically engineered mouse models, we identified the cytokine-TGF-β-signaling-dependent conversion of NK cells (CD49a−CD49b+Eomes+) into intermediate type 1 innate lymphoid cell (intILC1) (CD49a+CD49b+Eomes+) populations and ILC1 (CD49a+CD49b−Eomesint) populations in the tumor microenvironment. Strikingly, intILC1s and ILC1s were unable to control local tumor growth and metastasis, whereas NK cells favored tumor immunosurveillance. Experiments with an antibody that neutralizes the cytokine TNF suggested that escape from the innate immune system was partially mediated by TNF-producing ILC1s. Our findings provide new insight into the plasticity of group 1 ILCs in the tumor microenvironment and suggest that the TGF-β-driven conversion of NK cells into ILC1s is a previously unknown mechanism by which tumors escape surveillance by the innate immune system.

    更新日期:2017-08-22
  • Increased cathepsin S in Prdm1−/− dendritic cells alters the TFH cell repertoire and contributes to lupus
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-10
    Sun Jung Kim, Sebastian Schätzle, S Sohail Ahmed, Wolfgang Haap, Su Hwa Jang, Peter K Gregersen, George Georgiou, Betty Diamond

    Aberrant population expansion of follicular helper T cells (TFH cells) occurs in patients with lupus. An unanswered question is whether an altered repertoire of T cell antigen receptors (TCRs) is associated with such expansion. Here we found that the transcription factor Blimp-1 (encoded by Prdm1) repressed expression of the gene encoding cathepsin S (Ctss), a cysteine protease that cleaves invariant chains and produces antigenic peptides for loading onto major histocompatibility complex (MHC) class II molecules. The increased CTSS expression in dendritic cells (DCs) from female mice with dendritic cell–specific conditional knockout of Prdm1 (CKO mice) altered the presentation of antigen to CD4+ T cells. Analysis of complementarity-determining region 3 (CDR3) regions containing the β-chain variable region (Vβ) demonstrated a more diverse repertoire of TFH cells from female CKO mice than of those from wild-type mice. In vivo treatment of CKO mice with a CTSS inhibitor abolished the lupus-related phenotype and reduced the diversity of the TFH cell TCR repertoire. Thus, Blimp-1 deficiency in DCs led to loss of appropriate regulation of Ctss expression in female mice and thereby modulated antigen presentation and the TFH cell repertoire to contribute to autoimmunity.

    更新日期:2017-08-22
  • Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-24
    Yi Shen, Zhenke Wen, Yinyin Li, Eric L Matteson, Jison Hong, Jörg J Goronzy, Cornelia M Weyand

    Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells—specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. ATPlopyruvatelo conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoration of pyruvate production or inhibition of fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their proarthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites.

    更新日期:2017-08-22
  • MLL4 prepares the enhancer landscape for Foxp3 induction via chromatin looping
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-31
    Katarzyna Placek, Gangqing Hu, Kairong Cui, Dunfang Zhang, Yi Ding, Ji-Eun Lee, Younghoon Jang, Chaochen Wang, Joanne Elizabeth Konkel, Jiuzhou Song, Chengyu Liu, Kai Ge, Wanjun Chen, Keji Zhao

    MLL4 is an essential subunit of the histone H3 Lys4 (H3K4)-methylation complexes. We found that MLL4 deficiency compromised the development of regulatory T cells (Treg cells) and resulted in a substantial decrease in monomethylated H3K4 (H3K4me1) and chromatin interaction at putative gene enhancers, a considerable portion of which were not direct targets of MLL4 but were enhancers that interacted with MLL4-bound sites. The decrease in H3K4me1 and chromatin interaction at the enhancers not bound by MLL4 correlated with MLL4 binding at distant interacting regions. Deletion of an upstream MLL4-binding site diminished the abundance of H3K4me1 at the regulatory elements of the gene encoding the transcription factor Foxp3 that were looped to the MLL4-binding site and compromised both the thymic differentiation and the inducible differentiation of Treg cells. We found that MLL4 catalyzed methylation of H3K4 at distant unbound enhancers via chromatin looping, which identifies a previously unknown mechanism for regulating the T cell enhancer landscape and affecting Treg cell differentiation.

    更新日期:2017-08-22
  • Translation is actively regulated during the differentiation of CD8+ effector T cells
    Nat. Immunol. (IF 21.506) Pub Date : 2017-07-17
    Koichi Araki, Masahiro Morita, Annelise G Bederman, Bogumila T Konieczny, Haydn T Kissick, Nahum Sonenberg, Rafi Ahmed

    T cells undergo myriad changes after antigenic activation. Araki and colleagues show that CD8+ T cells exert dynamic control of mRNA translation during differentiation into effector and memory cells.

    更新日期:2017-08-22
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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