Local changes in lipid environment of T cell receptor microclusters regulate membrane binding by the CD3epsilon cytoplasmic domain (P1103)

Abstract

Abstract The CD3epsilon and zeta cytoplasmic domains of the T cell receptor bind to the inner leaflet of the plasma membrane, and a previous NMR structure showed that both tyrosines of the CD3epsilon Immuno-tyrosine based activation motif partition into the bilayer. Electrostatic interactions between acidic phospholipids and clusters of basic CD3epsilon residues were previously shown to be essential for CD3epsilon and zeta membrane binding. Phosphatidylserine is the most abundant negatively charged lipid on the inner leaflet of the plasma membrane and makes a major contribution to membrane binding by the CD3epsilon cytoplasmic domain. Here we show that T cell receptor triggering by peptide-MHC complexes induces dissociation of the CD3epsilon cytoplasmic domain from the plasma membrane. Release of the CD3epsilon cytoplasmic domain from the membrane is accompanied by a substantial focal reduction in negative charge and phosphatidylserine density in T cell receptor microclusters. The localized reduction in phosphatidylserine density is explained by reduced diffusion of this lipid into synapses. These changes in the lipid composition of T cell receptor microclusters even occur when receptor signaling is blocked with a Src kinase inhibitor. Local changes in the lipid composition of the microclusters thus render the CD3epsilon cytoplasmic domain accessible during early stages of T cell activation.