IL-10 Receptor Signaling Empowers Regulatory T Cells to Control Th17 Responses and Protect from GN

<jats:p> <jats:bold>Background</jats:bold> 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.</jats:p> <jats:p> <jats:bold>Methods</jats:bold> 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.</jats:p> <jats:p> <jats:bold>Results</jats:bold> Compared with controls, mice with IL-10Ra<jats:sup>−/−</jats:sup> 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<jats:sup>+</jats:sup> Treg17 cells. Indeed, the capacity for direct <jats:italic toggle="yes">in vitro</jats:italic> suppression of Th17 responses by IL-10Ra<jats:sup>−/−</jats:sup> Tregs was significantly impaired. As underlying pathology, analyses conducted <jats:italic toggle="yes">in vitro</jats:italic> and <jats:italic toggle="yes">in vivo</jats:italic> using double-fluorescent reporter mice revealed strikingly decreased IL-10 production by IL-10Ra<jats:sup>−/−</jats:sup> Tregs. To assess, whether reduced IL-10 could explain the hyper Th17 phenotype, competitive cotransfer experiments were performed. Supporting our concept, IL-10Ra<jats:sup>−/−</jats:sup> T cells differentiated into Th17 cells at much higher frequencies than wild type T cells did during GN.</jats:p> <jats:p> <jats:bold>Conclusions</jats:bold> 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 <jats:italic toggle="yes">via</jats:italic> direct and indirect mechanisms. IL-10R thus may be a promising therapeutic target for the treatment of GN.</jats:p>