Cholesterol Metabolism in Regulatory T cell Function

About This Grant

ABSTRACT Increased Treg T cell receptor (TCR) signaling is correlated with increased Foxp3+ regulatory T cell (Treg) function in organ specific autoimmunity. In the context of autoimmunity, both Tregs and autoimmune T cells target similar self-antigens, potentially increasing competition for TCR ligands. We propose that Tregs possess cell-intrinsic features that can increase their competition for antigen. Our preliminary data suggest that Tregs have higher levels of cholesterol within their cell membrane compared to conventional effector T cells, which correlate with tetramer binding, TCR signaling, and might increase relative Treg antigenic sensitivity and competition for antigen in vivo. It is well established that Tregs exhibit distinct metabolic profiles skewed towards fatty acid oxidation. Our intriguing new observations suggest that cholesterol metabolism impacts plasma membrane composition and TCR activation in Tregs. Furthermore, our data suggest that lipid metabolism could be manipulated to improve Treg function. This proposal will test the hypothesis that cholesterol metabolism is regulated by the transcription factor Foxp3 and can be increased to boost regulatory T cell function. We will begin addressing this hypothesis by pursuing two specific aims: 1) Test the specific role of recently identified regulator of cholesterol metabolism Spring1 in Treg function, and 2) Assess the impact of exogenous cholesterol uptake on Treg suppressive function. The objective of this proposal is to establish whether we can manipulate Treg function through cholesterol metabolism. The proposed research is significant, because it will determine Treg- specific regulation of cholesterol metabolism and its effect on Treg function in autoimmune and inflammatory models with implications for cancer, metabolic and heart disease.