Transcriptional control of ILC3 function – finally something different between T cells and ILCs
RAR-related orphan receptor gt (RORgt) directs differentiation of pro-inflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases. However, RORgt-dependent group 3 innate lymphoid cells (ILC3s) provide essential immunity and tissue protection in the intestine, suggesting that targeting RORgt could also result in impaired host defense to infection or enhanced tissue damage. To assess the impact of RORgt inhibition on intestinal adaptive and innate responses, transient chemical inhibition of ROR-gt was used in vivo in the context of intestinal infection of mice with Citrobacter rodentium. Surprisingly, whilst inhibitors reduced cytokine production from TH17 cells, ILC3 production of both IL-17A and IL-22 was preserved. Inducible deletion of RORgt in mature ILC3s also did not impair cytokine responses in the steady state or during infection and ILC3 were able to persist in some tissues for many weeks following loss of RORgt expression. In contrast, inducible deletion of RORgt in mature CD4 T cells ablated TH17 responses. Finally, pharmacologic inhibition of RORgt provided therapeutic benefit in mouse models of intestinal inflammation, and reduced the frequencies of TH17 cells but not ILC3s isolated from primary intestinal samples of individuals with inflammatory bowel disease (IBD). Collectively, these results reveal differential requirements for RORgt in the maintenance of TH17 cell versus ILC3 responses, and suggest that transient inhibition of RORgt is a safe and effective therapeutic approach during intestinal inflammation.
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