Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol

Abstract

Most adaptive immune responses require the activation of specific T cells through the T cell antigen receptor–CD3 complex (TCR). Here we show that cholesterol sulfate (CS), a naturally occurring analog of cholesterol, inhibits CD3 ITAM phosphorylation, a crucial first step in T cell activation. Biochemical studies show that CS disrupted TCR multimers, apparently by displacing cholesterol, known to bind TCRβ. Moreover, CS-deficient mice displayed a heightened sensitivity to a self-antigen, whereas increasing CS content by intrathymic injection inhibited thymic selection, indicating that this molecule is an intrinsic regulator of thymocyte development. These results reveal a regulatory role for CS in TCR signaling and thymic selection, highlighting the importance of the membrane microenvironment in modulating cell surface receptor activation.

The Intracellular Cholesterol Landscape: Dynamic Integrator of the Immune Response

“…The reasons for the CD8 + T cell specificity of this mechanism remain unclear. Interestingly, cholesterol sulfate, which is produced in vivo by the action of Sult2b1 upon cholesterol, disrupts TCR nanoclusters, decreases TCR avidity, and inhibits TCR signaling by displacing TCRβ-bound cholesterol [70]. The extent to which Sult2b1-derived cholesterol sulfate may serve as a dynamic negative feedback regulator of TCR activation in vivo is uncertain, but evidence does suggest that it plays a role in thymic selection through differential regulation of TCR signaling in thymic T cell subsets [70].…”

“…Interestingly, cholesterol sulfate, which is produced in vivo by the action of Sult2b1 upon cholesterol, disrupts TCR nanoclusters, decreases TCR avidity, and inhibits TCR signaling by displacing TCRβ-bound cholesterol [70]. The extent to which Sult2b1-derived cholesterol sulfate may serve as a dynamic negative feedback regulator of TCR activation in vivo is uncertain, but evidence does suggest that it plays a role in thymic selection through differential regulation of TCR signaling in thymic T cell subsets [70]. Adding yet further complexity to the picture, it was recently reported that cholesterol binding may serve a dual role in TCR signaling, promoting TCR avidity, but also restraining spontaneous signaling by keeping the TCR in an inactive allosteric conformation that cannot be phosphorylated [71].…”

“…Taken together, it appears that cholesterol and its metabolites may serve to fine-tune the setpoint for TCR activation, possibly in a developmental, cell-specific, and stimulus-dependent manner. Given that TCR nanoclustering is known to increase from naive T cells to effector and memory T cells [70], it is intriguing to consider that developmentally regulated cholesterol metabolism may possibly interact with the environment in the programming of lymphocytes.…”

Impact of environmental factors on alloimmunity and transplant fate

“…Inhibition of ACAT1, a cholesterol esterification enzyme, led to increased CD8 + T cell cytotoxicity, TCR clustering, and TCR signaling (57). Further, cholesterol binds to the TCR-β chain (58), and the ratio of cholesterol to inhibitory cholesterol derivatives can potentiate TCR-mediated activation (59).…”

Impact of hyperlipidemia on alloimmunity

“…In addition to the effects of cholesterol on T cell proliferation, mounting evidence suggests that cholesterol is involved in TCR mediated signal transduction. Cholesterol binds to the TCR-β chain (104), and the ratio of cholesterol to inhibitory cholesterol derivatives can potentiate TCR receptor mediated activation (105). …”