Dysregulation of CD1d-Restricted Type II Natural Killer T Cells Leads to Spontaneous Development of Colitis in Mice

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 alpha-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/24 alpha beta Tg mice). RESULTS: CD1dTg/24 alpha beta Tg mice had reduced numbers of 24 alpha beta T cells compared with 24 alpha beta Tg mice, indicating that negative selection increases among type II NKT cells engaged by abundant self-antigen. The residual 24 alpha beta T cells in CD1dTg/24 alpha beta Tg mice had an altered surface phenotype and acquired a cytokine profile distinct from that of equivalent cells in 24 alpha beta Tg mice. Interestingly, CD1dTg/24 alpha beta 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. 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.