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Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol
Open accessAbstract
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 TCRβ. 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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Cites
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Kaech, S. M., Wherry, E. J., & Ahmed, R. (2002) · Nature Reviews Immunology · doi:10.1038/nri778 · Cited by 1,865
Regulation of human EGF receptor by lipids
Coskun, Ü., Grzybek, M., Drechsel, D., & Simons, K. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105666108 · Cited by 316
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Wang, Q., Zhu, T., Miao, N., Qu, Y., Wang, Z., Chao, Y., Wang, J., Wu, W., Xu, X., Xu, C., et al. (2022) · The EMBO Journal · doi:10.15252/embj.2022110636 · Cited by 45
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Metadata
- Authors
- Wang, F., Beck-García, K., Zorzin, C., Schamel, W. W. A., & Davis, M. M.
- Venue
- Nature Immunology
- Published
- 2016-05-23
- Volume
- 17
- Issue
- 7
- Pages
- 844-850
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W2396071402
- Cited by
- 199
- References
- 2
- FWCI
- 8.75
- Type
- journal article
- Language
- en
- Open access
- green
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- Wang, F., Beck-García, K., Zorzin, C., Schamel, W. W. A., & Davis, M. M. (2016). Inhibition of T cell receptor signaling by cholesterol sulfate, a naturally occurring derivative of membrane cholesterol. Nature Immunology. https://doi.org/10.1038/ni.3462
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