PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21
PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21
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DOI：
10.1172/jci.insight.130062
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发表时间：
2019-10-17
期刊：
影响因子：
8
通讯作者：
Rao, Deepak A.
中科院分区：
文献类型：
--
作者：
Bocharnikov, Alexandra, V;Keegan, Joshua;Rao, Deepak A.
系统性红斑狼疮（SLE）是一种以病理性T细胞-B细胞相互作用和自身抗体产生为特征的自身免疫性疾病。确定SLE中驱动B细胞应答的T细胞群可以设计特异性靶向病理细胞亚群的疗法。在这里，我们评估了来自多个队列的52名SLE患者循环中的CD 4（+）T细胞表型，并鉴定了高度扩增的PD-1（hi）CXCR 5-CD 4（+）T细胞群。细胞计数、转录组学和功能测定证明，来自SLE患者的PD-1（hi）CXCR 5-CD 4（+）T细胞是T外周辅助（Tph）细胞，一种通过IL-21刺激B细胞应答的CXCR 5- T细胞群。Tph细胞的频率，而不是T滤泡辅助细胞（Tfh）细胞，与SLE患者的临床疾病活动性和CD 11 c（+）B细胞的频率相关。PD-1（hi）CD 4（+）T细胞存在于狼疮性肾炎的肾脏中，并与肾脏中的B细胞数量相关。IL-21中和和CRISPR介导的MAF缺失都消除了Tph细胞在体外诱导记忆B细胞分化成浆母细胞的能力。这些发现表明Tph细胞在SLE中作为高度扩增的T细胞群，并提示Tph细胞在刺激病理性B细胞应答中起关键作用。
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4(+) T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1(hi)CXCR5-CD4(+) T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1(hi)CXCR5-CD4(+) T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c(+) B cells in SLE patients. PD-1(hi)CD4(+) T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.