Journal
NATURE IMMUNOLOGY
Volume 17, Issue 7, Pages 844-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3462
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Funding
- US National Institutes of Health [R01 AI022511, U19 AI 090019, U19-AI057229]
- Howard Hughes Medical Institute
- Deutsche Forschungsgemeinschaft [EXC294, SCHA 976/2-1]
- Excellence Initiative of the Deutsche Forschungsgemeinschaft (Spemann Graduate School) [GSC-4]
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Most adaptive immune responses require the activation of specific T cells through the T cell antigen receptor (TCR)-CD3 complex. 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. In biochemical studies, CS disrupted TCR multimers, apparently by displacing cholesterol, which is known to bind TCR beta. Moreover, CS-deficient mice showed 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.
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