A novel self-regulatory mechanism of Th17 cells controls autoimmune uveitis through interleukin-24

Abstract

Abstract The Th17 response is critical in driving inflammation and is associated with many autoimmune diseases. However, clinical trials targeting the Th17 signature cytokine, IL-17A in some autoimmune diseases, including uveitis, have been disappointing. We investigated the role of IL-17A in determining the pathogenicity of uveitogenic Th17 cells. Unexpectedly, IL-17A deficiency in these cells did not reduce the severity of uveitis in recipient mice. We found that IL-17A deficient Th17 cells produced elevated amounts of other Th17-related cytokines, i.e. IL-17F, GM-CSF and IL-22. RNA-seq analysis and the follow up in-vitro experiments revealed that IL-17A exerts a negative feedback on Th17 cells by inducing them to produce IL-24, which in turn suppresses the production of Th17-related cytokines in an autocrine fashion. In vivo results showed that IL-24 treatment of recipients ameliorated Th17-induced adoptive EAU, and conversely, silencing IL-24 expression in retina-specific Th17 cells increased their pathogenicity, supporting the relevance of this pathway in vivo. Mechanistic studies confirmed that IL-17A activates the NFkB signalling pathway in Th17 cells, whereas site mutagenesis at the NFkB binding sites In IL-24 promoter abrogates the IL-17A-induced IL-24 expression. In vitro experiments implicated SOCS 1 and 3 in the downstream effects of IL-24. Importantly, we also observed a similar inhibitory IL-17A/IL-24 circuit in polarized human Th17 cells. We conclude that IL-17A exerts a negative feedback on Th17 cells by inducing autocrine IL-24, which limits their expression of other Th17-lineage cytokines and dampens their pathogenicity.