Group 1 CD1-restricted Autoreactive T cells in Inflammatory Disease

Psoriasis is a chronic inflammatory skin disease affecting 1-3% of the population worldwide. Several studies have shown a significant association between psoriasis and hyperlipidemia, a well-established risk factor for cardiovascular disease, suggesting these conditions may share common inflammatory pathways. While multiple immune cell types have been implicated in the pathogenesis of psoriasis, including conventional CD4+ and CD8+ T cells, the potential contributions of lipid autoreactive CD1-restricted T cells to psoriasis pathogenesis remain elusive. CD1 molecules bind and present lipid antigens to T cells. These antigens include mammalian self-lipids and foreign lipids derived from specific microorganisms. In humans, the CD1 family consists of group 1 CD1 molecules (CD1a, -b, and c) and the group 2 CD1 molecule CD1d. Mice lack group 1 CD1, but do express CD1d. The unique binding specificity of CD1 suggests a potential role for CD1 molecules in the presentation of modified lipids to autoreactive T cells in hyperlipidemic conditions. However, due to the lack of a suitable animal model, the role of autoreactive group 1 CD1-restricted T cells in hyperlipidemia-associated inflammatory diseases is unknown. To overcome this limitation, we have generated a double transgenic mouse model that expresses human group 1 CD1 molecules and a group 1 CD1-autoreactive T cell receptor. In this study, we crossed this novel transgenic mouse to the ApoE-deficient background to study the role of autoreactive group 1 CD1-restricted T cells in hyperlipidemia. Interestingly, the presence of group 1 CD1-autoreactive T cells under hyperlipidmic conditions resulted in the mice developing severe psoriasis-like skin inflammation. While this finding suggests that autoreactive group 1 CD1-restricted T cells contribute to the pathogenesis of hyperlipidemia-induced skin inflammation, when, where and how these T cells are activated is unclear. Therefore, in Aim 1, we propose to investigate the mechanisms by which group 1 CD1-restricted autoreactive T cells contribute to skin inflammation and the kinetics of activation and localization of lipid autoreactive T cells during the course of disease. In Aim 2, we propose to examine how these T cells are activated by deciphering the nature of the lipid antigens presented by group 1 CD1 molecules during disease progression and further examining whether hyperlipidemia affects DC function, thereby resulting in group 1 CD1-autoreactive T cell activation. Collectively, these studies will lead to a better understanding of how group 1 CD1-restricted autoreactive T cells contribute to hyperlipidemia-associated inflammatory diseases and provide the basis for manipulating these T cells to uncover new strategies for therapeutic intervention for psoriasis and other inflammatory disorders.