| Summary: | 博士 === 國立臺灣大學 === 動物學研究所 === 100 === CD1d-restricted NKT cells are a unique subset of immunoregulatory T cells
further divided into two subtypes. Type I NKT cells express semi-invariant TCR and can be detected using α-GalCer/CD1d tetramer, whereas type II NKT cells express diverse TCR and cannot be directly identified. The developmental requirements and molecular mechanisms that regulate type I NKT cells are distinct from those of conventional T cells. CD1d-expressing hematopoietic cells are shown to be required for mediating the positive selection of type I NKT cells. In addition, signaling lymphocytic activation molecule-associated protein (SAP) is an adaptor molecular which has also been shown to be important for the development and function of type I NKT cells. Unlike type I NKT cells which have been well investigated, studies of the development and mechanisms of which regulate type II NKT cells are poorly understood. Furthermore, clinical studies on several mouse models of inflammatory bowel disease (IBD) have revealed a complex role for type I NKT cells in the development of IBD while type II NKT cells appear to contribute to intestinal inflammation in individuals suffering from ulcerative colitis. In this study, I used a TCR transgenic mouse model (24αβTg) to study a dominant type II NKT cell population. I demonstrate that the CD1d-expressing hematopoietic cells meditate the efficient selection of type II NKT using bone marrow chimeras. Given the similar developmental requirements sharing between type I NKT and type II NKT cells, I sought to address whether SAP is also required for the development and function of type II NKT cells. Therefore, I generated 24αβTg/SAP-/- mice and observed that type II NKT cells have an immature phenotype and impaired cytokine IFN-γ and IL-4 production in the thymus. The reduction of IFN-γ in type II NKT cells is correlated with a significantly reduced expression of T-bet and Eomes transcription factor. Furthermore, to address whether the dysregulation of type II NKT cells caused by increased CD1d expression can contribute to the pathogenesis of IBD, I crossed 24αβTg mice with CD1Tg mice that express higher levels of CD1d in all cell types. In CD1dTg/24αβTg mice, I observed reduced 24αβT cell numbers, suggesting that type II NKT cells undergo enhanced negative selection when engaged by abundant self-antigen or self-ligands. Additionally, the residual 24αβT cells in CD1dTg/24αβTg mice exhibited an altered surface phenotype and acquired a cytokine profile distinct from that of equivalent cells in 24αβTg mice. Interestingly, CD1dTg/24αβTg mice spontaneously developed IBD and adoptive transfer experiments confirmed that type II NKT cells that develop in the context of increased CD1d expression are pathogenic. Collectively, these findings comprise the first evidence of the CD1d-expressing hematopoietic cells in mediating the selection of type II NKT cells and reveal the pivotal role of SAP in regulating the normal development and mature phenotype and function of type II NKT cells. In addition, I have demonstrated that aberrant type II NKT cell responses directly contribute to intestinal inflammation, highlighting the importance of CD1d expression level in the development and regulation of type II NKT cells.
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