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Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3{varepsilon} cytoplasmic domain.

Gagnon E, Schubert DA, Gordo S, Chu HH, Wucherpfennig KW

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute; and 2 Program in Immunology, Harvard Medical School, Boston, MA 02115.

The CD3ε and ζ cytoplasmic domains of the T cell receptor bind to the inner leaflet of the plasma membrane (PM), and a previous nuclear magnetic resonance structure showed that both tyrosines of the CD3ε immunoreceptor tyrosine-based activation motif partition into the bilayer. Electrostatic interactions between acidic phospholipids and clusters of basic CD3ε residues were previously shown to be essential for CD3ε and ζ membrane binding. Phosphatidylserine (PS) is the most abundant negatively charged lipid on the inner leaflet of the PM and makes a major contribution to membrane binding by the CD3ε cytoplasmic domain. Here, we show that TCR triggering by peptide-MHC complexes induces dissociation of the CD3ε cytoplasmic domain from the plasma membrane. Release of the CD3ε cytoplasmic domain from the membrane is accompanied by a substantial focal reduction in negative charge and available PS in TCR microclusters. These changes in the lipid composition of TCR microclusters even occur when TCR signaling is blocked with a Src kinase inhibitor. Local changes in the lipid composition of TCR microclusters thus render the CD3ε cytoplasmic domain accessible during early stages of T cell activation.

J. Exp. Med. 2012;209(13):2423-39.

Pubmed ID: 23166358

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