Self-tolerance to an ileal antigen requires both IL-17A and IFNγ in mice predisposed to spontaneous ileocolitis

Abstract Homeostasis in the ileum involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4+T cell responses, we used TCR transgenic tools to breed “Bigenic” mice that spontaneously produced CD4+T cells reactive to a model antigen expressed in the ileum. Bigenic mice were grossly similar to control littermates at weaning. By DOL 50, the Bigenic cohort showed reduced weight, increased circulating CD4+TEM frequencies and TH17-associated ileal hyperplasia. An extended natural history study to DOL 150 revealed that only half of Bigenic mice exhibit chronic wasting disease marked by mucosal infiltration by TH17 and TH1 cells expressing non-transgenic clonotypes, colitis and loss of ileal crypt hyperplasia. By contrast, adult Bigenic mice with normal growth maintained the TH17-associated ileal crypt hyperplasia phenotype and additionally accumulated ileal-reactive Treg cells. Adoptive transfer of nTreg cells prevented both ileal crypt hyperplasia and ileal-reactive Treg cell accumulation. Both IL-17A and IFNγ were required for ileal-reactive Treg accumulation and regulation of ileal-reactive CD4+Tconv cells. Ifng−/− Bigenic mice also exhibited an IL-23R-dependent, acutely progressive wasting disease that was >95% penetrant by DOL 50. Thus, our studies identify an IL-17A and IFNγ-dependent homeostatic inflammatory process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.