A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate
A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate
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DOI：
10.1038/s41591-018-0254-9
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发表时间：
2019-01-01
期刊：
影响因子：
82.9
通讯作者：
Pascual, Virginia
中科院分区：
文献类型：
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作者：
Caielli, Simone;Veiga, Diogo Troggian;Pascual, Virginia
了解自身抗体产生的机制将加速自身免疫性疾病（如系统性红斑狼疮（SLE））的治疗靶点识别（1）。滤泡辅助性T细胞（T-FH细胞）长期以来一直与SLE发病机制有关。然而，SLE患者中的一部分自身抗体是未突变的，支持自身反应性B细胞也在生殖中心外分化（2）。在这里，我们描述了一个CXCR 5（-）CXCR 3（+）程序性死亡1（PD 1）（hi）CD 4（+）辅助性T细胞群，它不同于T-FH细胞，并在SLE血液和增生性狼疮肾炎个体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，这是由琥珀酸激发的反向电子传递的结果。此外，它们通过IL-10和琥珀酸盐独立于IL-21提供B细胞帮助。用氧化线粒体DNA激活的浆细胞样树突状细胞（一种不同类型的干扰素样toll样受体9配体）引发初始CD 4（+）T细胞后，在体外产生类似的细胞（3）。靶向这一通路可能会减弱SLE滤泡外体液反应的启动和/或持续。
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 (T-FH 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 centers(2). Here, we describe a CXCR5(-)CXCR3(+) programmed death 1 (PD1)(hi)CD4(+) helper T cell population distinct from T-FH 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 ligand(3). Targeting this pathway might blunt the initiation and/or perpetuation of extrafollicular humoral responses in SLE.