The Role of Group 1 CD1-Restricted T Cells in Atherosclerosis

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DESCRIPTION (provided by applicant): Atherosclerosis is a complex inflammatory disease characterized by the retention and modification of lipids within the vascular wall. Recently, the role of distinct T cell subsets in the development of atherosclerosis has been evaluated. One particular T cell subsets recognizes lipid antigens presented by CD1 family of antigen presenting molecules. In humans, this family consists of the group 1 CD1 molecules CD1a, b, and c, and the group 2 molecule CD1d. Mice lack group 1 CD1, but express CD1d. The unique binding specificity of CD1 suggests a potential role for the CD1 molecules in the presentation of modified lipids to T cells involved in atherogenesis. Indeed, CD1d-restricted invariant NKT cells have been shown to play a proatherogenic role in murine models of atherosclerosis. Moreover, elevated expression levels of group 1 CD1 have been observed in atherosclerotic plaques found in humans, and group 1 CD1-restricted T cells can be activated by macrophage-derived foam cells in vitro. While these findings suggest that group 1 CD1 molecules and their cognate T cells contribute to the pathogenesis of this disease, the functional role of group 1 CD1-restricted T cells in atherosclerosis has not been directly studied due to the lack of a suitable animal model. To overcome this limitation, my lab has generated transgenic mouse models that express both the human group 1 CD1 molecules and group 1 CD1-specific T cell receptors. In this study, we propose to utilize these novel transgenic mouse models to test the hypothesis that group 1 CD1-restricted T cells contribute to atherogenesis. In Aim 1, we propose to determine the overall contribution of group 1 CD1-restricted responses to atherogenesis in a diet-induced atherosclerosis model and to investigate the mechanisms by which group 1 CD1-restricted autoreactive T cells contribute to disease pathogenesis. In Aim 2, we propose to examine whether hyperlipidemic conditions associated with atherosclerosis affect the activation and function of group 1 CD1-restricted T cells, as well as the mechanisms mediating such effects. Collectively, these studies will lead to a better understanding of how group 1 CD1-restricted autoreactive T cells contribute to atherosclerosis and whether they can be manipulated to modulate the progression of the disease.