Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE)1. Follicular helper T cells (TFH cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers2. Here, we describe a CXCR5-CXCR3+ programmed death 1 (PD1)hiCD4+ helper T cell population distinct from TFH cells and expanded in both SLE blood and the tubulointerstitial areas of individuals with proliferative lupus nephritis. These cells produce interleukin-10 (IL-10) and accumulate mitochondrial reactive oxygen species as the result of reverse electron transport fueled by succinate. Furthermore, they provide B cell help, independently of IL-21, through IL-10 and succinate. Similar cells are generated in vitro upon priming naive CD4+ T cells with plasmacytoid dendritic cells activated with oxidized mitochondrial DNA, a distinct class of interferogenic toll-like receptor 9 ligand3. Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.

中文翻译：

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在狼疮血液中扩增的 CD4+ T 细胞群通过白细胞介素 10 和琥珀酸盐提供 B 细胞帮助。

了解自身抗体开发的潜在机制将加速自身免疫性疾病如系统性红斑狼疮 (SLE)1 的治疗靶点鉴定。滤泡辅助 T 细胞 (TFH 细胞) 长期以来一直与 SLE 发病机制有关。然而，SLE 患者中的一小部分自身抗体是未突变的，这支持了自身反应性 B 细胞也在生发中心之外分化。在这里，我们描述了一个与 TFH 细胞不同的 CXCR5-CXCR3+ 程序性死亡 1 (PD1)hiCD4+ 辅助 T 细胞群，并在 SLE 血液和增殖性狼疮肾炎患者的肾小管间质区域中扩增。这些细胞产生白细胞介素 10 (IL-10) 并积累线粒体活性氧，这是由琥珀酸驱动的反向电子传输的结果。此外，它们还提供 B 细胞帮助，独立于 IL-21，通过 IL-10 和琥珀酸。在用氧化的线粒体 DNA（一类独特的干扰性 toll 样受体 9 配体 3）激活的浆细胞样树突状细胞启动幼稚 CD4+ T 细胞后，会在体外产生类似的细胞。针对该途径可能会减弱 SLE 中滤泡外体液反应的启动和/或持续存在。