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BACH2 represses effector programs to stabilize T_(reg)-mediated immune homeostasis

机译：BACH2抑制效应子程序以稳定T_（reg）介导的免疫稳态

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摘要

编码转录因子BACH2的一个位点内的多态性，与包括哮喘、多发性硬化、克罗恩氏病、腹腔病和1-型糖尿病开内的若干种过敏和自体免疫疾病相关。这篇论文识别出了BACH2可能用来帮助自体免疫的一个机制。Roychoudhuri等人解释了BACH2是怎样通过稳定调控性T-细胞的分化来抑制其他细胞命运从而限制自体免疫的。这此发现说明，BACH2起CD4 T-细胞分化的一个调控因子的作用，通过控制耐受与免疫之间的平衡来防止炎症。%Through their functional diversification, distinct lineages of CD4~+ T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4~+ T cells. BACH2 was required for efficient formation of regulatory (T_(reg)) cells and consequently for suppression of lethal inflammation in a manner that was T_(reg)-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during T_(reg) polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within T_H1, T_H2 and T_H17 cell lineages. These findings identify BACH2 as a key regulator of CD4~+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.
机译：编码转录因子BACH2的一个位点内的多态性，与包括哮喘、多发性硬化、克罗恩氏病、腹腔病和1-型糖尿病开内的若干种过敏和自体免疫疾病相关。这篇论文识别出了BACH2可能用来帮助自体免疫的一个机制。Roychoudhuri等人解释了BACH2是怎样通过稳定调控性T-细胞的分化来抑制其他细胞命运从而限制自体免疫的。这此发现说明，BACH2起CD4 T-细胞分化的一个调控因子的作用，通过控制耐受与免疫之间的平衡来防止炎症。%Through their functional diversification, distinct lineages of CD4~+ T cells can act to either drive or constrain immune-mediated pathology. Transcription factors are critical in the generation of cellular diversity, and negative regulators antagonistic to alternate fates often act in conjunction with positive regulators to stabilize lineage commitment. Genetic polymorphisms within a single locus encoding the transcription factor BACH2 are associated with numerous autoimmune and allergic diseases including asthma, Crohn's disease, coeliac disease, vitiligo, multiple sclerosis and type 1 diabetes. Although these associations point to a shared mechanism underlying susceptibility to diverse immune-mediated diseases, a function for BACH2 in the maintenance of immune homeostasis has not been established. Here, by studying mice in which the Bach2 gene is disrupted, we define BACH2 as a broad regulator of immune activation that stabilizes immunoregulatory capacity while repressing the differentiation programs of multiple effector lineages in CD4~+ T cells. BACH2 was required for efficient formation of regulatory (T_(reg)) cells and consequently for suppression of lethal inflammation in a manner that was T_(reg)-cell-dependent. Assessment of the genome-wide function of BACH2, however, revealed that it represses genes associated with effector cell differentiation. Consequently, its absence during T_(reg) polarization resulted in inappropriate diversion to effector lineages. In addition, BACH2 constrained full effector differentiation within T_H1, T_H2 and T_H17 cell lineages. These findings identify BACH2 as a key regulator of CD4~+ T-cell differentiation that prevents inflammatory disease by controlling the balance between tolerance and immunity.

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  • 来源
    《Nature》 |2013年第7455期|506-510395|共6页
  • 作者

    Rahul Roychoudhuri; Kiyoshi Hirahara; Kambiz Mousavi; David Clever; Christopher A. Klebanoff; Michael Bonelli; Giuseppe Sciume; Hossein Zare; Golnaz Vahedi; Barbara Dema; Zhiya Yu; Hui Liu; Hayato Takahashi; Mahadev Rao; Pawel Muranski; Joseph G. Crompton; George Punkosdy; Davide Bedognetti; Ena Wang; Victoria Hoffmann; Juan Rivera; Francesco M. Marincola; Atsushi Nakamura; Vittorio Sartorelli; Yuka Kanno; Luca Gattinoni; Akihiko Muto; Kazuhiko Igarashi; John J. OShea; Nicholas P. Restifo;

  • 作者单位

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.;

    Molecular Immunology and inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS),NIH, Bethesda, Maryland 20892, USA.;

    Laboratory of Muscle Stem Cellsand Gene Regulation, NIAMS.NIH.Bethesda, Maryland 20892, USA.;

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.;

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.;

    Molecular Immunology and inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS),NIH, Bethesda, Maryland 20892, USA.;

    Molecular Immunology and inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS),NIH, Bethesda, Maryland 20892, USA.;

    Laboratory of Muscle Stem Cellsand Gene Regulation, NIAMS.NIH.Bethesda, Maryland 20892, USA.;

    Molecular Immunology and inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS),NIH, Bethesda, Maryland 20892, USA.;

    Laboratory of Molecular Immunogenetics, NIAMS, NIH, Bethesda, Maryland 20892, USA.;

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.;

    Department of Transfusion Medicine, NIH, Bethesda, Maryland 20892, USA.;

    Molecular Immunology and inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS),NIH, Bethesda, Maryland 20892, USA.;

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.;

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.;

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.;

    National Institutes of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA.;

    Department of Transfusion Medicine, NIH, Bethesda, Maryland 20892, USA.;

    Department of Transfusion Medicine, NIH, Bethesda, Maryland 20892, USA.;

    Division of Veterinary Resources, NIH, Bethesda, Maryland 20892, USA.;

    Laboratory of Molecular Immunogenetics, NIAMS, NIH, Bethesda, Maryland 20892, USA.;

    Department of Transfusion Medicine, NIH, Bethesda, Maryland 20892, USA, Sidra Medical and Research Centre, Doha, Qatar.;

    Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.,CREST, Japan Science and Technology Agency, Sendai 980-8575, Japan.;

    Laboratory of Muscle Stem Cellsand Gene Regulation, NIAMS.NIH.Bethesda, Maryland 20892, USA.;

    Molecular Immunology and inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS),NIH, Bethesda, Maryland 20892, USA.;

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.;

    Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.,CREST, Japan Science and Technology Agency, Sendai 980-8575, Japan.;

    Department of Biochemistry, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.,CREST, Japan Science and Technology Agency, Sendai 980-8575, Japan.;

    Molecular Immunology and inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS),NIH, Bethesda, Maryland 20892, USA.;

    Center for Cancer Research, National Cancer Institute, National Institutes of Health (NIH), Bethesda, Maryland 20892, USA, NIH Center for Regenerative Medicine, NIH, Bethesda, Maryland 20892, USA. tPresent address: Department of Advanced Allergology of the Airway, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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