A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFN gamma to generate self-tolerance and prevent colitis

作者：Jeschke Jonathan C; Mayne Christopher G; Ziegelbauer Jennifer; DeCiantis Christopher L; Singh Selina; Kumar Suresh N; Suchi Mariko; Iwakura Yoichiro; Drobyski William R; Salzman Nita H; Williams Calvin B^*

来源：Mucosal Immunology, 2018, 11(4): 1127-1137.

DOI：10.1038/s41385-018-0023-6

Homeostasis in the ileum, which is commonly disrupted in patients with Crohn's disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4(+) T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4(+) T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of T(H)17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by T(H)17 and T(H)1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit T(H)17-associated ileal crypt hyperplasia and additionally accumulated ileal-reactive Treg cells. Both IL-17A and IFN gamma were protective, as their deficiency precluded ileal-reactive Treg accumulation and exacerbated colitic disease. IL-23R blockade prevented progression to colitis, whereas nTreg cell transfers prevented colitic disease, ileal crypt hyperplasia and ileal-reactive Treg accumulation. Thus, our studies identify an IL-17A and IFN gamma-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.

• 出版日期2018-7