Divergent functions of IL-17-family cytokines in DSS colitis: Insights from a naturally-occurring human mutation in IL-17F

The IL-17 family is structurally distinct from other cytokine subclasses. IL-17A and IL-17F, the most closely related of this family, form homodimers and an IL-17AF heterodimer. While IL-17A and IL-17F exhibit similar activities in many settings, in others their functions are divergent. To better understand the function of IL-17F in vivo, we created mice harboring a mutation in Il17f originally described in humans with unexplained chronic mucosal candidiasis (Ser-65-Leu). We evaluated Il17fS65L/S65L mice in DSS-colitis, as this is one of the few settings where IL-17A and IL-17F exhibit opposing activities. Specifically, IL-17A is protective of the gut epithelium, a finding that was revealed when trials of anti-IL-17A biologics in Crohn's disease failed and recapitulated in many mouse models of colitis. In contrast, mice lacking IL-17F are resistant to DSS-colitis, partly attributable to alterations in intestinal microbiota that mobilize Tregs. Here we report that Il17fS65L/S65L mice do not phenocopy Il17f-/- mice in DSS colitis, but rather exhibited a worsening disease phenotype much like Il17a-/- mice. Gut inflammation in Il17fS65L/S65L mice correlated with reduced Treg accumulation and lowered intestinal levels of Clostridium cluster XIV. Unexpectedly, the protective DSS-colitis phenotype in Il17f-/- mice could be reversed upon co-housing with Il17fS65L/S65L mice, also correlating with Clostridium cluster XIV levels in gut. Thus, the Il17fS65L/S65L phenotype resembles an IL-17A deficiency more closely than IL-17F deficiency in the setting of DSS colitis.