Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering

Eszter Molnár, Mahima Swamy, Martin Holzer, Katharina Beck-García, Remigiusz Worch, Christoph Thiele, Gernot Guigas, Kristian Boye, Immanuel F. Luescher, Petra Schwille, Rolf Schubert, Wolfgang W.A. Schamel

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69 Citations (Scopus)

Abstract

The T-cell antigen receptor (TCR) exists in monomeric and nanoclustered forms independently of antigen binding. Although the clustering is involved in the regulation of T-cell sensitivity, it is unknown how the TCR nanoclusters form. We show that cholesterol is required for TCR nanoclustering in T cells and that this clustering enhances the avidity but not the affinity of the TCR-antigen interaction. Investigating the mechanism of the nanoclustering, we found that radioactive photocholesterol specifically binds to the TCRβ chain in vivo. In order to reduce the complexity of cellular membranes, we used a synthetic biology approach and reconstituted the TCR in liposomes of defined lipid composition. Both cholesterol and sphingomyelin were required for the formation of TCR dimers in phos-phatidylcholine-containing large unilamellar vesicles. Further, the TCR was localized in the liquid disordered phase in giant unilamellar vesicles. We propose a model in which cholesterol and sphingomyelin binding to the TCRβ chain causes TCR dimerization. The lipid-induced TCR nanoclustering enhances the avidity to antigen and thus might be involved in enhanced sensitivity of memory compared with naive T cells. Our work contributes to the understanding of the function of specific nonannular lipid-membrane protein interactions.

Original languageEnglish
Pages (from-to)42664-42674
Number of pages11
JournalJournal of Biological Chemistry
Volume287
Issue number51
Early online date22 Oct 2012
DOIs
Publication statusPublished - 14 Dec 2012

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    Molnár, E., Swamy, M., Holzer, M., Beck-García, K., Worch, R., Thiele, C., Guigas, G., Boye, K., Luescher, I. F., Schwille, P., Schubert, R., & Schamel, W. W. A. (2012). Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. Journal of Biological Chemistry, 287(51), 42664-42674. https://doi.org/10.1074/jbc.M112.386045