title: Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3ε cytoplasmic domain.
abstract: 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.
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. etienne.gagnon@umontreal.ca
authors.forename: Etienne
authors.initials: E
authors.lastname: Gagnon
authors.forename: David A
authors.initials: DA
authors.lastname: Schubert
authors.forename: Susana
authors.initials: S
authors.lastname: Gordo
authors.forename: H Hamlet
authors.initials: HH
authors.lastname: Chu
authors.forename: Kai W
authors.initials: KW
authors.lastname: Wucherpfennig
mesh_terms: D017252:CD3 Complex / Q000737:chemistry* / Q000378:metabolism*; D002478:Cells, Cultured; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D015804:HLA-DR4 Antigen / Q000378:metabolism; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors / Q000378:metabolism; D008563:Membrane Lipids / Q000737:chemistry* / Q000378:metabolism*; D010718:Phosphatidylserines / Q000737:chemistry / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction; D055672:Static Electricity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D017252:CD3 Complex; C115335:CD3E protein, human; D015804:HLA-DR4 Antigen; D008563:Membrane Lipids; D010718:Phosphatidylserines; D011948:Receptors, Antigen, T-Cell; D018799:Intercellular Adhesion Molecule-1; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)