RORγ-Expressing Th17 Cells Induce Murine Chronic Intestinal Inflammation via Redundant Effects of IL-17A and IL-17F

Background and Aims: IL-17-producing CD4(+) Thelper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)gamma, which regulates Th17 differentiation, in chronic intestinal inflammation. Methods: Using an adoptive transfer model of colitis, we compared the colitogenic potential of wildtype, interleukin-17A (IL-17A)-, IL-17F-, IL-22-, and ROR gamma-deficient CD4(+)CD25(-) T cells in RAG1-null mice. Results: Adoptive transfer of IL-17A-, IL-17F-, or IL-22-deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of ROR gamma-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of ROR gamma-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F-null (but not wild-type) T cells with a neutralizing anti-IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F. Conclusions., We have identified a crucial role of ROR gamma-expressing Th17 cells in chronic intestinal inflammation. ROR gamma controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target ROR gamma or a combination of anti-IL-17A and anti-IL-17F might be developed as therapeutics for chronic colitis.