IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjogren's syndrome
IL-10-producing regulatory B cells restrain the T follicular helper cell response in primary Sjogren's syndrome
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产生 IL-10 的调节性 B 细胞抑制原发性干燥综合征中滤泡辅助 T 细胞的反应
DOI：
10.1038/s41423-019-0227-z
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发表时间：
2019-12-01
影响因子：
24.1
通讯作者：
Lu, Liwei
中科院分区：
文献类型：
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作者：
Lin, Xiang;Wang, Xiaohui;Lu, Liwei
滤泡辅助性T（Tfh）细胞数量增多与包括原发性干燥综合征（pSS）在内的自身免疫性疾病的发生发展有关，但在自身免疫发病机制中Tfh细胞应答是如何受到调控的，目前仍知之甚少。在此，我们首先发现，在pSS患者及实验性干燥综合征（ESS）小鼠中，白细胞介素10（IL - 10）阳性的调节性B（Breg）细胞数量与Tfh细胞应答及疾病活动度呈负相关。此外，我们在人和小鼠的Tfh细胞及其前体细胞上均检测到IL - 10受体的高表达。在体外培养实验中，IL - 10通过促进信号转导及转录激活因子5（STAT5）磷酸化来抑制人和小鼠Tfh细胞的分化。通过过继转移实验方法及双光子活体成像技术，我们发现，在ESS发展过程中，与过继转移野生型B细胞的RAG - 2 - / - 小鼠相比，过继转移IL - 10缺陷型B细胞的RAG - 2 - / - 小鼠，其引流颈部淋巴结中Tfh细胞数量显著增多，且T细胞向B细胞滤泡的归巢增强。在ESS小鼠中，IL - 10产生减少的CD19 + CD1d高表达CD5 + Breg细胞对T细胞增殖的抑制作用严重受损。同样，pSS患者的CD19 + CD24 + CD38高表达Breg细胞IL - 10产生显著减少，在抑制自体Tfh细胞扩增方面其抑制功能存在缺陷。此外，过继转移产生IL - 10的Breg细胞可显著抑制ESS小鼠的Tfh细胞应答，并改善ESS进展。综上所述，这些研究结果表明，产生IL - 10的Breg细胞在pSS发展过程中对效应性Tfh细胞应答的抑制起着关键作用。
Increased numbers of T follicular helper (Tfh) cells have been implicated in the development of autoimmune diseases including primary Sjogren's syndrome (pSS), but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear. Here, we first found negative correlations between IL-10(+) regulatory B (Breg) cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjogren's syndrome (ESS). Moreover, we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice. In culture, IL-10 suppressed human and murine Tfh cell differentiation by promoting STATS phosphorylation. By using an adoptive transfer approach and two-photon live imaging, we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2-/- mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2-/- mice transferred with wild-type B cells. In ESS mice, CD19(+)CD1d(hi)CD5(+) Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation. Consistently, CD19(+)CD24(+)CD38(hi) Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion. Furthermore, the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice. Together, these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development.