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

RAR-related orphan receptor γt (ROR-γt) directs differentiation of pro-inflammatory T helper 17 (T(H)17) cells and is a potential therapeutic target in chronic autoimmune and inflammatory diseases(1–3). However, ROR-γt-dependent group 3 innate lymphoid cells (ILC3s) provide essential immunity and tissue protection in the intestine(4–11), 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 T(H)17 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 T(H)17 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 T(H)17 cell versus ILC3 responses, and suggest that transient inhibition of ROR-γt is a safe and effective therapeutic approach during intestinal inflammation

Th1 responses in vivo require cell-specific provision of OX40L dictated by environmental cues

The OX40-OX40L axis is a crucial component of the costimulatory requirement of CD4 T cell responses. Here, the authors show context and cell type specific expression of OX40L for driving Th1 cell generation during acute and chronic models of infection