The role of CD1d-restricted type II NKT cells in the pathogenesis of inflammatory bowel disease (93.10)

Abstract

CD1d is an MHC class Ib molecule that is specialized to present lipid antigens to NKT cells. Two subsets of NKT cells have been identified: type I NKT cells express an invariant TCR α chain while type II NKT cells express a more diverse TCR repertoire. Recent studies have shown that a specific pattern of CD1d expression is required for proper development and function of type I NKT cells. However, little is known about the regulation and selection of type II NKT cells as there is no method for direct detection of these cells. To address whether changes in CD1d expression patterns can regulate the function of type II NKT cells, we have generated a double transgenic mouse model, CD1dTg/24αβTg, that expresses high levels of CD1d as well as a TCR isolated from the type II NKT cell clone 24αβ. Total numbers of 24αβ T cells are significantly reduced in CD1dTg/24αβTg mice, suggesting that type II NKT cells undergo negative selection when engaged by abundant self-antigen. The remaining 24αβ T cells exhibit an altered surface phenotype and produce increased levels of inflammatory cytokines compared to equivalent cells that develop in a wild type B6 background. Interestingly, CD1dTg/24αβTg mice spontaneously develop inflammatory bowel disease (IBD) characterized by extensive colonic inflammation. Our studies highlight the importance of CD1d expression levels in the regulation of type II NKT cells and reveal a potential role for type II NKT cells in the pathogenesis of IBD.