Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol.
Wang F, Beck-García K, Zorzin C, Schamel WW, Davis MM.
In a previous BIOSS publications we have shown that cholesterol promotes nano-clustering of the T cell antigen receptor (TCR) by binding to the TCRβ subunit. In a collaborative work with the group of Mark Davis from Sanford, Cailfornia, we have now focussed on cholesterol sulfate, a naturally occurring analog of cholesterol. We show that cholesterol sulfate inhibits ligand-induced phosphorylation of the TCR. Using synthetic biology approaches we demonstrate that cholesterol sulfate disrupts the TCR nanoclusters. In fact, cholesterol sulfate displaced cholesterol from TCRβ. Cholesterol sulfate deficient mice show an increased sensitivity to a self-antigen, whereas increasing cholesterol sulfate levels inhibits selection of T cell precursors, called thymocytes in the thymus. Thus, this cholesterol derivative is an intrinsic regulator of T cell development. Together, these results show a novel regulatory role for cholesterol sulfate in TCR nanoclustering and activation, highlighting the importance of the membrane microenvironment in modulating cell surface receptor activation.
