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Dysregulation of CD1d-restricted type II natural killer T cells leads to spontaneous development of colitis in mice.

Journal article
Authors Chia-Min Liao
Michael I Zimmer
Sharmila Shanmuganad
Hon-Tsen Yu
Susanna Cardell
Chyung-Ru Wang
Published in Gastroenterology
Volume 142
Issue 2
Pages 326-34.e1-2
ISSN 1528-0012
Publication year 2012
Published at Institute of Biomedicine, Department of Microbiology and Immunology
Pages 326-34.e1-2
Language en
Links dx.doi.org/10.1053/j.gastro.2011.10...
Keywords Animals, Antigens, CD1d, metabolism, Colitis, Ulcerative, immunology, metabolism, pathology, Cytokines, metabolism, Disease Models, Animal, Flow Cytometry, Mice, Mice, Transgenic, Natural Killer T-Cells, metabolism
Subject categories Microbiology in the medical area

Abstract

BACKGROUND & AIMS: CD1d-restricted natural killer (NK) T cells are a subset of immunoregulatory T cells that comprise type I (express the semi-invariant T-cell receptor [TCR] and can be detected using the α-galactosylceramide/CD1d tetramer) and type II (express diverse TCRs and cannot be directly identified). Studies in mouse models of inflammatory bowel disease revealed a complex role for type I NKT cells in the development of colitis. Type II NKT cells have been associated with intestinal inflammation in patients with ulcerative colitis. METHODS: To investigate whether dysregulation of type II NKT cells, caused by increased expression of CD1d, can contribute to colitis, we generated transgenic mice that express high levels of CD1d and a TCR from an autoreactive, type II NKT cell (CD1dTg/24αβTg mice). RESULTS: CD1dTg/24αβTg mice had reduced numbers of 24αβ T cells compared with 24αβTg mice, indicating that negative selection increases among type II NKT cells engaged by abundant self-antigen. The residual 24αβ T cells in CD1dTg/24αβTg mice had an altered surface phenotype and acquired a cytokine profile distinct from that of equivalent cells in 24αβTg mice. Interestingly, CD1dTg/24αβTg mice spontaneously developed colitis; adoptive transfer experiments confirmed that type II NKT cells that develop in the context of increased CD1d expression are pathogenic. CONCLUSIONS: Aberrant type II NKT cell responses directly contribute to intestinal inflammation in mice, indicating the importance of CD1d expression levels in the development and regulation of type II NKT cells.

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