Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.
Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis.
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DOI：
10.1038/nature20810
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发表时间：
2017-02-01
期刊：
影响因子：
64.8
通讯作者：
Brenner MB
中科院分区：
文献类型：
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作者：
Rao DA;Gurish MF;Marshall JL;Slowikowski K;Fonseka CY;Liu Y;Donlin LT;Henderson LA;Wei K;Mizoguchi F;Teslovich NC;Weinblatt ME;Massarotti EM;Coblyn JS;Helfgott SM;Lee YC;Todd DJ;Bykerk VP;Goodman SM;Pernis AB;Ivashkiv LB;Karlson EW;Nigrovic PA;Filer A;Buckley CD;Lederer JA;Raychaudhuri S;Brenner MB
CD4+ T细胞是自身免疫病理的中心介质；然而，确定它们在特定自身免疫性疾病中的关键效应功能仍然具有挑战性。病变组织内的致病性CD4+ T细胞可通过近期激活标记物的表达来识别。在这里，我们使用细胞计数法评估类风湿关节炎（RA）患者关节组织中的活化T细胞，类风湿关节炎是一种慢性免疫介导的关节炎，影响高达1%的人群。该方法揭示了RA滑膜中PD-1hi CXCR5- CD4+ T细胞的显著扩增。这些细胞没有耗尽。相反，多维细胞术、转录组学和功能分析确定了PD-1hi CXCR5-“外周辅助”T （Tph）细胞群，这些细胞表达能够帮助B细胞的因子，包括IL-21、CXCL13、ICOS和MAF。与PD-1hi CXCR5+ T滤泡辅助细胞（Tfh）一样，Tph细胞通过IL-21和slamf5相互作用诱导浆细胞分化。然而，全球转录组学可以将Tph细胞从Tfh细胞中分离出来，Tph细胞中Bcl6和Blimp-1的表达发生改变，趋化因子受体（如CCR2、CX3CR1和CCR5）的独特表达可直接迁移到炎症部位。Tph细胞在病理炎症的非淋巴组织中表现出独特的促进B细胞反应和抗体产生的能力。
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. Here, we used mass cytometry to evaluate activated T cells in joint tissue from patients with rheumatoid arthritis (RA), a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a strikingly expanded population of PD-1hi CXCR5- CD4+ T cells in RA synovium. These cells are not exhausted. Rather, multidimensional cytometry, transcriptomics, and functional assays define a population of PD-1hi CXCR5- ‘peripheral helper’ T (Tph) cells that express factors enabling B cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hi CXCR5+ T follicular helper (Tfh) cells, Tph cells induce plasma cell differentiation in vitro via IL-21 and SLAMF5-interactions. However, global transcriptomics robustly separate Tph cells from Tfh cells, with altered expression of Bcl6 and Blimp-1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in Tph cells. Tph cells appear uniquely poised to promote B cell responses and antibody production within pathologically inflamed non-lymphoid tissues.