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首页> 外文期刊>Nature >Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis
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Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis

机译：病理扩展的外周血T辅助细胞亚群驱动类风湿关节炎的B细胞

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摘要

CD4(+) T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4(+) T cells within affected tissues may be identified by expression of markers of recent activation(1). Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population(2). This approach revealed a markedly expanded population of PD-1(hi)CXCR5(-)CD4(+) T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1(hi)CXCR5(-) 'peripheral helper' T (T-PH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1(hi)CXCR5(+) T follicular helper cells, T-PH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between T-PH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in T-PH cells. T-PH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
机译：CD4（+）T细胞是自身免疫病理的主要介质。然而，在特定的自身免疫性疾病中定义其关键效应子功能仍然具有挑战性。受影响组织中的致病性CD4（+）T细胞可通过表达近期激活的标记物来鉴定（1）。在这里，我们使用流式细胞仪分析类风湿性关节炎患者的关节组织中活化的T细胞，类风湿性关节炎是一种慢性免疫介导的关节炎，可影响高达1％的人口（2）。这种方法显示类风湿性关节炎患者滑膜中PD-1（hi）CXCR5（-）CD4（+）T细胞的数量明显增加。然而，尽管PD-1高表达，但这些细胞并未耗尽。相反，我们使用多维细胞计数法，转录组学和功能测定方法，定义了PD-1（hi）CXCR5（-）“外围辅助细胞” T（T-PH）细胞群体，这些细胞表达的因子可促进B细胞帮助，包括IL- 21，CXCL13，ICOS和MAF。像PD-1（hi）CXCR5（+）T卵泡辅助细胞一样，T-PH细胞通过IL-21分泌和SLAMF5相互作用在体外诱导浆细胞分化（参考文献3、4）。然而，全球转录组学突显了T-PH细胞和T滤泡辅助细胞之间的差异，包括BCL6和BLIMP1表达的改变以及趋化因子受体的独特表达，这些趋化因子受体直接迁移到T-PH中的发炎部位，例如CCR2，CX3CR1和CCR5。细胞。 T-PH细胞似乎具有独特的平衡能力，可以促进B细胞反应和病理发炎的非淋巴组织内的抗体产生。

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  • 来源
    《Nature》 |2017年第7639期|110-114|共5页
  • 作者

    Rao Deepak A.; Gurish Michael F.; Marshall Jennifer L.; Slowikowski Kamil; Fonseka Chamith Y.; Liu Yanyan; Donlin Laura T.; Henderson Lauren A.; Wei Kevin; Mizoguchi Fumitaka; Teslovich Nikola C.; Weinblatt Michael E.; Massarotti Elena M.; Coblyn Jonathan S.; Helfgott Simon M.; Lee Yvonne C.; Todd Derrick J.; Ykerk Vivian P. B.; Goodman Susan M.; Pernis Alessandra B.; Ivashkiv Lionel B.; Karlson Elizabeth W.; Nigrovic Peter A.; Filer Andrew; Buckley Christopher D.; Lederer James A.; Raychaudhuri Soumya; Renner Michael B. B.;

  • 作者单位

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Harvard Univ, Cambridge, MA 02138 USA;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA;

    Univ Birmingham, Queen Elizabeth Hosp, Inst Inflammat & Ageing, Rheumatol Res Grp, Birmingham B15 2WB, W Midlands, England|Harvard Med Sch, Boston, MA 02115 USA|Boston Childrens Hosp, Divis Immunol, Boston, MA 02115 USA;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA|Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Partners Ctr Personalized Genet Med, Boston, MA 02115 USA;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA;

    Harvard Med Sch, Boston, MA 02115 USA|Harvard Univ, Bioinformat & Integrat Genom, Cambridge, MA 02138 USA|Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Univ Birmingham, Queen Elizabeth Hosp, Inst Inflammat & Ageing, Rheumatol Res Grp, Birmingham B15 2WB, W Midlands, England|Harvard Univ, Bioinformat & Integrat Genom, Cambridge, MA 02138 USA|Karolinska Inst, Reumatol Unit, S-17176 Stockholm, Sweden;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Harvard Med Sch, Boston, MA 02115 USA|Boston Childrens Hosp, Divis Immunol, Boston, MA 02115 USA;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA|Karolinska Univ Hosp Solna, S-17176 Stockholm, Sweden;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Harvard Med Sch, Boston, MA 02115 USA;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|Karolinska Inst, Reumatol Unit, S-17176 Stockholm, Sweden;

    Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA|Hosp Special Surg, Autoimmun & Inflammat Program, New York, NY 10021 USA|Karolinska Univ Hosp Solna, S-17176 Stockholm, Sweden|Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PT, Lancs, England;

    Boston Childrens Hosp, Divis Immunol, Boston, MA 02115 USA|Hosp Special Surg, Div Rheumatol, 535 E 70th St, New York, NY 10021 USA;

    Univ Birmingham, Queen Elizabeth Hosp, Inst Inflammat & Ageing, Rheumatol Res Grp, Birmingham B15 2WB, W Midlands, England|Harvard Med Sch, Boston, MA 02115 USA|Harvard Univ, Cambridge, MA 02138 USA|Harvard Univ, Biol & Biomed Sci, Cambridge, MA 02138 USA|Hosp Special Surg, David Z Rosensweig Genom Res Ctr, New York, NY 10021 USA;

    Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA|Harvard Med Sch, Boston, MA 02115 USA|Boston Childrens Hosp, Divis Immunol, Boston, MA 02115 USA|Hosp Special Surg, Autoimmun & Inflammat Program, New York, NY 10021 USA|Karolinska Univ Hosp Solna, S-17176 Stockholm, Sweden;

    Harvard Med Sch, Boston, MA 02115 USA|Univ Birmingham, Queen Elizabeth Hosp, Inst Inflammat & Ageing, Rheumatol Res Grp, Birmingham B15 2WB, W Midlands, England|MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA|Hosp Special Surg, Arthrit & Tissue Degenerat Program, New York, NY USA|Karolinska Univ Hosp Solna, S-17176 Stockholm, Sweden|Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PT, Lancs, England;

    Harvard Univ, Cambridge, MA 02138 USA|Hosp Special Surg, Autoimmun & Inflammat Program, New York, NY 10021 USA;

    Harvard Med Sch, Boston, MA 02115 USA|Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA|Cornell Univ, Weill Cornell Med Coll, New York, NY 10021 USA|Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA|Karolinska Inst, Reumatol Unit, S-17176 Stockholm, Sweden;

    Hosp Special Surg, Div Rheumatol, 535 E 70th St, New York, NY 10021 USA|Hosp Special Surg, Autoimmun & Inflammat Program, New York, NY 10021 USA;

    Hosp Special Surg, David Z Rosensweig Genom Res Ctr, New York, NY 10021 USA|Boston Childrens Hosp, Divis Immunol, Boston, MA 02115 USA|Univ Manchester, Inst Inflammat & Repair, Manchester M13 9PT, Lancs, England;

    Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA 02115 USA|MIT, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA|Harvard Univ, Cambridge, MA 02138 USA|Hosp Special Surg, Arthrit & Tissue Degenerat Program, New York, NY USA;

    Hosp Special Surg, Div Rheumatol, 535 E 70th St, New York, NY 10021 USA;

    Hosp Special Surg, David Z Rosensweig Genom Res Ctr, New York, NY 10021 USA;

    Hosp Special Surg, David Z Rosensweig Genom Res Ctr, New York, NY 10021 USA;

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