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A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis. Mucosal Immunol 2018 07;11(4):1127-1137

Date

05/08/2018

Pubmed ID

29728642

Pubmed Central ID

PMC6571016

DOI

10.1038/s41385-018-0023-6

Scopus ID

2-s2.0-85046438531   1 Citation

Abstract

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 TH17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by TH17 and TH1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit TH17-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.

Author List

Jeschke JC, Mayne CG, Ziegelbauer J, DeCiantis CL, Singh S, Kumar SN, Suchi M, Iwakura Y, Drobyski WR, Salzman NH, Williams CB

Authors

William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Suresh Kumar PhD Associate Professor in the Pathology department at Medical College of Wisconsin
Nita H. Salzman MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
Mariko Suchi MD, PhD Associate Professor in the Pathology department at Medical College of Wisconsin
Calvin B. Williams MD, PhD Chief, Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Colitis
Crohn Disease
Disease Models, Animal
Humans
Hyperplasia
Ileum
Interferon-gamma
Interleukin-17
Mice
Mice, Transgenic
Receptors, Antigen, T-Cell, alpha-beta
Self Tolerance
Th1 Cells
Th17 Cells
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a