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

ABSTRACT: 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 ?-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.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/24??Tg mice).CD1dTg/24??Tg mice had reduced numbers of 24?? T cells compared with 24??Tg mice, indicating that negative selection increases among type II NKT cells engaged by abundant self-antigen. The residual 24?? T cells in CD1dTg/24??Tg mice had an altered surface phenotype and acquired a cytokine profile distinct from that of equivalent cells in 24??Tg mice. Interestingly, CD1dTg/24??Tg mice spontaneously developed colitis; adoptive transfer experiments confirmed that type II NKT cells that develop in the context of increased CD1d expression are pathogenic.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.

SUBMITTER: Liao CM 

PROVIDER: S-EPMC3267843 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature