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 localizatio 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.
Hyperlipidemia, a well-known risk factor for cardiovascular disease, is also associated with an elevated risk of several autoimmune diseases, highlighting a potential role for lipid antigen-specific T cells in disease pathogenesis. This study proposes to examine the role of human group 1 CD1-autoreactive T cells in psoriasis, a common autoimmune disorder of the skin. Although mice do not naturally express group 1 CD1 molecules, we have generated transgenic mouse strains that express both human group 1 CD1 molecules and group 1 CD1-specific T cell receptors, making these models uniquely suited for this project. We anticipate that these studies will provide insight into the mechanistic link between hyperlipidemia and psoriasis as well as other hyperlipidemia-related inflammatory diseases, and may illuminate new therapeutic targets for treating these diseases.
| Bagchi, Sreya; Genardi, Samantha; Wang, Chyung-Ru (2018) Linking CD1-Restricted T Cells With Autoimmunity and Dyslipidemia: Lipid Levels Matter. Front Immunol 9:1616 |
| Bagchi, Sreya; He, Ying; Zhang, Hong et al. (2017) CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice. J Clin Invest 127:2339-2352 |
| Seeliger, Jessica; Moody, D Branch (2016) Monstrous Mycobacterial Lipids. Cell Chem Biol 23:207-209 |
| Siddiqui, Sarah; Visvabharathy, Lavanya; Wang, Chyung-Ru (2015) Role of Group 1 CD1-Restricted T Cells in Infectious Disease. Front Immunol 6:337 |
