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

Autor: Jeschke JC; Department of Pediatrics, Section of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Mayne CG; Department of Pediatrics, Section of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.; Department of Biology, Viterbo University, La Crosse, WI, 54601, USA., Ziegelbauer J; Department of Pediatrics, Section of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., DeCiantis CL; Department of Pediatrics, Section of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Singh S; Department of Pediatrics, Section of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Kumar SN; Department of Pathology, Division of Pediatric Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Suchi M; Department of Pathology, Division of Pediatric Pathology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Iwakura Y; Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, 278-0022, Japan.; Core Research for Evolutionary Science and Technology, Japan Science and Technology Agency, Saitama, 332-0012, Japan., Drobyski WR; Department of Medicine, Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Salzman NH; Department of Pediatrics, Section of Gastroenterology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA., Williams CB; Department of Pediatrics, Section of Rheumatology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA. cwilliam@mcw.edu.
Jazyk: angličtina
Zdroj: Mucosal immunology [Mucosal Immunol] 2018 Jul; Vol. 11 (4), pp. 1127-1137. Date of Electronic Publication: 2018 May 04.
DOI: 10.1038/s41385-018-0023-6
Abstrakt: 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.
Databáze: MEDLINE
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