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

• Published in: Mucosal immunology Vol. 11; no. 4; pp. 1127 - 1137
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2018; Elsevier Limited
• Subjects: Allergology; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; CD4 antigen; Chronic wasting disease; Colitis; Colitis - immunology; Crohn Disease - immunology; Crohn's disease; Disease Models, Animal; Gastroenterology; Helper cells; Homeostasis; Humans; Hyperplasia; Ileum; Ileum - pathology; Immunological tolerance; Immunology; Inflammatory bowel disease; Interferon-gamma - metabolism; Interleukin 23; Interleukin-17 - metabolism; Lymphocytes T; Mice; Mice, Transgenic; Mucosa; Receptors, Antigen, T-Cell, alpha-beta - genetics; Rodents; Self Tolerance; T cell receptors; Th1 Cells - immunology; Th17 Cells - immunology; Transgenic mice; Transmissible spongiform encephalopathy; γ-Interferon
• ISSN: 1933-0219; 1935-3456
• 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 IFNγ 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 IFNγ-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.