Inflammatory bowel diseases
Inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, are incurable chronic conditions that result from uncontrolled gut inflammation. Pathogenic Th17 cells, characterised by production of IL-17 in the absence of IL-10, are thought to contribute to this inflammation, but in humans, antibody-mediated blockade of IL-17 is an ineffective IBD therapy. We hypothesized that anti-IL-17 antibodies may not completely disable Th17 cells, and moreover could have deleterious effects on Th17-like FOXP3+ regulatory T cells (Th17-like Tregs). We investigated whether pharmacological inhibition of RORγt, the Th17 cell lineage-defining transcription factor, was an alternate approach to inhibit Th17 cells. Addition of BMS-336, a small molecule RORγt inhibitor, to human peripheral Th17 (CXCR3–CCR4+CCR6+) and Th17.1 (CXCR3+CCR4+CCR6+) cells inhibited expression of RORγt target genes in a dose-dependent manner. Similarly, IL-17 production by laminar propria mononuclear cells, isolated from IBD and non-IBD subjects, was significantly inhibited by BMS-336. BMS-336 also inhibited expression of RORγt-regulated genes in Th17-like Tregs (CD4+CD25hiCD127loCXCR3–CCR4+CCR6+) without affecting expression of FOXP3 or their suppressive function. Interestingly, RORγt inhibition significantly increased production of IL-10 in Th17-like Tregs. When cultured under proinflammatory conditions, Th17-like Tregs were destabilised, as evidenced by loss of FOXP3 expression and re-methylation of the Treg specific demethylation region; this destabilisation was repressed by BMS-336. Overall, these results demonstrate that inhibition of RORγt is a promising approach to selectively inhibit Th17 cells, and in parallel enhance the function Th17-like Tregs by increasing IL-10 production and restraining their lineage instability in the presence of inflammation.