Background:
The Th17 response has been associated with autoimmune diseases in patients and in animal models. IL-17A is recognized as the Th17 signature cytokine and IL-17-producing T cells are pathogenic effectors in models of autoimmunity, including experimental autoimmune uveitis (EAU). Paradoxically, however, IL-17A treatment given to EAU-challenged mice was reported to ameliorate the disease (PMID: 19234216) and clinical trials targeting IL-17A in uveitis have been largely disappointing (PMID: 25648267).
Methods:
We investigated susceptibility to EAU in interphotoreceptor retinoid binding(IRBP)-immunized mice on an IL-17A-/- background. Additionally, T cells from IL-17A-sufficient and deficient IRBP T cell receptor transgenic R161H mice were polarized under Th17 conditions and were adoptively transferred to WT recipients to examine their cytokine profile and their ability to induce EAU.
Results:
Surprisingly, IL-17A-/- EAU mice developed essentially undiminished uveitis. IL-17A-/- R161H T cells, polarized to Th17 and infused into wild type recipients, induced similar disease to IL-17A-sufficient R161H T cells. These Th17-polarized IL-17A-/- R161H T cells produced elevated amounts of other Th17 lineage cytokines, namely, IL-17F, GM-CSF and IL-22, and this was reversed by supplementing the cultures with recombinant IL-17A. RNAseq analysis revealed that the IL-17A-/- T cells expressed lower levels of IL-24 compared to their IL-17A sufficient counterparts. Mechanistic studies in vitro indicated a negative feedback loop where IL-17A induces Th17 cells to produce IL-24, which subsequently suppresses production of Th17 lineage cytokines. Studies in vivo showed that injection of recombinant IL-24 ameliorated adoptive Th17-induced EAU, and conversely, silencing IL-24 expression in the adoptively transferred Th17 cells increased their pathogenicity and enhanced disease severity.
Conclusions:
Our data suggest that IL-17A exerts a negative feedback on Th17 cells by inducing IL-24, which limits the expression of Th17-related cytokines and dampens Th17 effector pathogenicity.