Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis
Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis
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DOI：
10.1038/nm.3432
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发表时间：
2014-01-01
期刊：
影响因子：
82.9
通讯作者：
Takayanagi, Hiroshi
中科院分区：
文献类型：
--
作者：
Komatsu, Noriko;Okamoto, Kazuo;Takayanagi, Hiroshi
自身免疫性疾病通常是由于调节性 T (T-reg) 细胞和产生白细胞介素 17 (IL-17) 的辅助性 T (T(H)17) 细胞之间的不平衡所致；后一种细胞的起源仍然很大程度上未知。 Foxp3对于Treg细胞的抑制功能是不可或缺的，但Foxp3的稳定性一直存在争议。在这里，我们证明源自 Foxp3(+) T 细胞的 T(H)17 细胞在自身免疫性关节炎的发病机制中发挥着关键作用。在关节炎条件下，CD25(lo)Foxp3(+)CD4(+) T细胞失去Foxp3表达(本文称为exFoxp3细胞)并转分化为T(H)17细胞。命运图谱分析显示，表达 IL-17 的 exFoxp3 T (exFoxp3 T(H)17) 细胞在发炎关节中积累。 Foxp3(+)CD4(+) T细胞向T(H)17细胞的转化是由滑膜成纤维细胞衍生的IL-6介导的。这些 exFoxp3 T(H)17 细胞是比幼稚 CD4(+) T 细胞衍生的 T(H)17 细胞更有效的破骨细胞 T 细胞。值得注意的是，exFoxp3 T(H)17 细胞的特征是表达 Sox4、趋化因子（C-C 基序）受体 6 (CCR6)、趋化因子（C-C 基序）配体 20 (CCL20)、IL-23 受体 (IL-23R) 和 NF-κ B 配体受体激活剂 (RANKL，也称为 TNFSF11)。将具有自身反应性、抗原经历的 CD25(lo)Foxp3(+)CD4(+) T 细胞过继转移到小鼠体内，然后用胶原蛋白进行二次免疫，会加速关节炎的发作并增加关节炎的严重程度，并且与大多数转移的 T 细胞中 Foxp3 表达的丧失有关。我们在活动性类风湿关节炎（RA）受试者的滑膜中观察到IL-17（+）Foxp3（+）T细胞，这表明塑料Foxp3（+）T细胞有助于RA的发病机制。这些发现证实了 Foxp3 不稳定性在自身免疫中致病性 T(H)17 细胞生成中的病理学重要性。
Autoimmune diseases often result from an imbalance between regulatory T (T-reg) cells and interleukin-17 (IL-17)-producing T helper (T(H)17) cells; the origin of the latter cells remains largely unknown. Foxp3 is indispensable for the suppressive function of Treg cells, but the stability of Foxp3 has been under debate. Here we show that T(H)17 cells originating from Foxp3(+) T cells have a key role in the pathogenesis of autoimmune arthritis. Under arthritic conditions, CD25(lo)Foxp3(+)CD4(+) T cells lose Foxp3 expression (herein called exFoxp3 cells) and undergo transdifferentiation into T(H)17 cells. Fate mapping analysis showed that IL-17-expressing exFoxp3 T (exFoxp3 T(H)17) cells accumulated in inflamed joints. The conversion of Foxp3(+)CD4(+) T cells to T(H)17 cells was mediated by synovial fibroblast-derived IL-6. These exFoxp3 T(H)17 cells were more potent osteoclastogenic T cells than were naive CD4(+) T cell-derived T(H)17 cells. Notably, exFoxp3 T(H)17 cells were characterized by the expression of Sox4, chemokine (C-C motif) receptor 6 (CCR6), chemokine (C-C motif) ligand 20 (CCL20), IL-23 receptor (IL-23R) and receptor activator of NF-kappa B ligand (RANKL, also called TNFSF11). Adoptive transfer of autoreactive, antigen-experienced CD25(lo)Foxp3(+)CD4(+) T cells into mice followed by secondary immunization with collagen accelerated the onset and increased the severity of arthritis and was associated with the loss of Foxp3 expression in the majority of transferred T cells. We observed IL-17(+)Foxp3(+) T cells in the synovium of subjects with active rheumatoid arthritis (RA), which suggests that plastic Foxp3(+) T cells contribute to the pathogenesis of RA. These findings establish the pathological importance of Foxp3 instability in the generation of pathogenic T(H)17 cells in autoimmunity.