Suppression of IL-17F, but not of IL-17A, provides protection against colitis by inducing Treg cells through modification of the intestinal microbiota

The cytokines IL-17A and IL-17F have 50% amino-acid identity and bind the same receptor; however, their functional differences have remained obscure. Here we found that Il17f –/– mice resisted chemically induced colitis, but Il17a –/– mice did not, and that Il17f −/− CD45RB hi CD4 + T cells induced milder colitis in lymphocyte-deficient Rag2 –/– mice, accompanied by an increase in intestinal regulatory T cells (T reg cells). Clostridium cluster XIVa in colonic microbiota capable of inducing T reg cells was increased in both Il17f −/− mice and mice given transfer Il17f −/− T cells, due to decreased expression of a group of antimicrobial proteins. There was substantial production of IL-17F, but not of IL-17A, not only by naive T cells but also by various colon-resident cells under physiological conditions. Furthermore, antibody to IL-17F suppressed the development of colitis, but antibody to IL-17A did not. These observations suggest that IL-17F is an effective target for the treatment of colitis. The cytokines IL-17A and IL-17F bind via same receptor. Iwakura and colleagues demonstrate different functions for IL-17A and IL-17F in the gut, with the latter altering the production of antimicrobial peptides with consequent effects on the microbiota, the induction of T reg cells and immune-system homeostasis.