Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells

Abstract

RAR-related orphan receptor γt (ROR-γt) directs differentiation of pro-inflammatory T helper 17 (TH17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases1–3. However, ROR-γt-dependent group 3 innate lymphoid cells (ILC3s) provide essential immunity and tissue protection in the intestine4–11, suggesting that targeting ROR-γt could also result in impaired host defense to infection or enhanced tissue damage. Here, we demonstrate that transient chemical inhibition of ROR-γt in mice selectively reduces cytokine production from TH17 cells but not ILC3s in the context of intestinal infection with Citrobacter rodentium, resulting in preserved innate immunity. Transient genetic deletion of ROR-γt in mature ILC3s also did not impair cytokine responses in the steady state or during infection. Finally, pharmacologic inhibition of ROR-γt 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 ROR-γt in the maintenance of TH17 cell versus ILC3 responses, and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation.

Current and emerging therapeutic targets for IBD

“…Transcription factors regulating cytokine gene expression are potential future drug targets in IBD 119,120 . Theoretically, targeting such regu latory proteins might enable suppression of the produc tion of several proinflammatory cytokines at the same time.…”

“…Potential strategies for targeting include siRNA, DNAzymes and chemical inhibitors. A study published in 2016 used a chemical inhibitor of RORγt, a master transcription factor in T H 17 cells, for successful ther apy of experimental T cell dependent colitis in mice 120 . Furthermore, genetic RORγ deficiency of T cells pre vented T cell transfer of colitis in RAG knockout mice 84 .…”

Retinoic-acid-orphan-receptor-C inhibition suppresses Th17 cells and induces thymic aberrations

“…Hence, cpd 1 appears not to generally affect intestinal integrity despite potential changes in IL-17 production in the gut. Recently, it has been shown that pharmacological inhibition of RORC is therapeutically efficacious in a mouse model of intestinal inflammation and selectively reduces cytokine production from Th17 cells, but it preserves innate lymphoid cells in a mouse intestinal infection model (25). Genetic Rorc deficiency in mice causes strong perturbations of the immune system, as well as development of metastasizing thymic T cell lymphomas (1,10,11,12,14).…”

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease

“…Among Th cell subsets, Th17 cells have been implicated in the mediation of tissue destruction in a wide range of inflammatory diseases including inflammatory bowel disease (IBD) (7)(8)(9). In support of the functional relevance of Th17 cell biology in intestinal inflammation, specific targeting of the Th17 differentiation-regulating transcription factor RORγt limited experimental colitis (7,10). However, whether alloreactive Th17 cells promote GVHD-associated intestinal inflammation is a matter of controversy, since independent studies yielded partially contradictory results (7)(8)(9)(11)(12)(13)(14)(15).…”