Background Th17 cells are central pathogenic mediators of autoimmune disease, including many forms of GN. IL-10 receptor signaling (IL-10R) in regulatory T cells (Tregs) has been implicated in the downregulation of Th17 cells, but the underlying molecular mechanisms and functional relevance of this process remain unclear.

Methods We generated mice with Treg-specific IL-10Ra deficiency and subjected these mice to nephrotoxic serum–induced nephritis as a model of crescentic GN. Immune responses and Treg phenotypes were extensively analyzed.

Results Compared with controls, mice with IL-10Ra^−/− Tregs showed a spontaneously overshooting Th17 immune response. This hyper-Th17 phenotype was further boosted during GN and associated with aggravated renal injury. Notably, abrogation of IL-10Ra signaling in Tregs increased dendritic cell activation and production of Th17-inducing cytokines. In contrast, Treg trafficking and expression of chemokine receptor CCR6 remained unaffected, indicating mechanisms of Th17 control, differing from those of previously identified CCR6⁺ Treg17 cells. Indeed, the capacity for direct in vitro suppression of Th17 responses by IL-10Ra^−/− Tregs was significantly impaired. As underlying pathology, analyses conducted in vitro and in vivo using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra^−/− Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra^−/− T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN.

Conclusions IL-10R engagement optimizes Treg-mediated suppression of Th17 immunity. We hypothesize a feed-forward loop, in which IL-10Ra signaling reinforces IL-10 secretion by Tregs which potently controls Th17 development via direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.

背景Th17细胞是自身免疫性疾病（包括多种形式的GN）的中枢病原介质。调节性T细胞（Tregs）中的IL-10受体信号转导（IL-10R）与Th17细胞的下调有关，但该过程的潜在分子机制和功能相关性尚不清楚。

方法我们生成了Treg特异性IL-10Ra缺乏的小鼠，并将其作为新月形GN的模型进行肾毒性血清诱发的肾炎。免疫反应和Treg表型进行了广泛的分析。

结果与对照组相比，具有IL-10Ra ^-/- Treg的小鼠表现出自发性的Th17免疫应答超调。在GN期间，这种高Th17表型进一步增强，并伴有严重的肾脏损伤。值得注意的是，Tregs中IL-10Ra信号的废除增加了树突状细胞的激活和Th17诱导细胞因子的产生。相反，Treg的运输和趋化因子受体CCR6的表达仍然不受影响，表明Th17控制的机制不同于先前鉴定的CCR6 ⁺ Treg17细胞。的确，对于直接的能力在体外的通过IL-10RA的Th17应答的抑制^{- / -}的Treg被显著削弱。作为基础病理，体外分析并且使用双荧光报告基因小鼠体内实验显示，IL-10Ra ^-/- Tregs显着降低了IL-10的产生。为了评估是否降低的IL-10可以解释Th17的高表型，进行了竞争性共转移实验。支持我们的概念，IL-10Ra ^-/- T细胞分化成Th17细胞的频率比GN期间的野生型T细胞高得多。

结论IL-10R的参与优化了Treg介导的Th17免疫抑制。我们假设一个前馈回路，其中IL-10Ra信号通过Tregs增强IL-10分泌，而Tregs通过直接和间接机制有效地控制Th17的发育。因此，IL-10R可能是治疗GN的有希望的治疗靶标。