IL-17A inhibits expression of IL-17-ineage cytokines through a negative feedback loop involving IL-24 and controls autoimmune uveitis

Abstract

Purpose : 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, injection of IL-17 was shown by others to ameliorate the disease (PMID: 19234216).

Methods : Using a model of spontaneous uveitis in IRBP T cell receptor transgenic R161H mice, we investigated the susceptibility to disease of mice on an IL-17A^-/- background. Additionally, T cells from IL-17A-sufficient and deficient 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^-/- R161H mice developed essentially undiminished uveitis and IL-17^-/- R161H T cells, polarized to Th17 and infused into wild type recipients, induced similar disease to IL-17A sufficient R161H T cells. Interestingly, IL-17A^-/- R161H T cells polarized under Th17 conditions produced elevated amounts of other Th17-related cytokines, i.e. IL-17F, GM-CSF and IL-22. Supplementing these cultures with recombinant IL-17A normalized the elevated production of those cytokines. RNAseq analysis revealed that IL-17A^-/- T cells displayed lower IL-24 expression compared to their IL-17 sufficient counterparts. Mechanistic studies indicated a negative feedback loop where IL-17A induces Th17 cells to produce IL-24, which suppresses production of Th17 lineage cytokines. Finally, injection of recombinant IL-24 ameliorated adoptive Th17-induced EAU, and conversely, depletion of IL-24 in Th17 cells increased their pathogenicity and elevated disease severity.

Conclusions : These data suggest that: (a) IL-17A exerts a negative feedback on uveitogenic Th17 cells via IL-24 production, and (b) IL-24 limits the expression of other Th17-related cytokines and controls their pathogenicity.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.