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 Il17f(S65L/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 Cmhn'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 Il17f(S65L/S65L) mice do not phenocopy Il17f(-/-) mice in DSS colitis, but rather exhibited a worsening disease phenotype much like Il17a(-/-) mice. Gut inflammation in Il17f(S65L/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 Il17f(S65L/S65L) mice, also correlating with Clostridium cluster XIV levels in gut. Thus, the Il17f(S65L/S65L) phenotype resembles an IL-17A deficiency more closely than IL-17F deficiency in the setting of DSS colitis.