title: The CD3 zeta subunit contains a phosphoinositide-binding motif that is required for the stable accumulation of TCR-CD3 complex at the immunological synapse.
abstract: T cell activation involves a cascade of TCR-mediated signals that are regulated by three distinct intracellular signaling motifs located within the cytoplasmic tails of the CD3 chains. Whereas all the CD3 subunits possess at least one ITAM, the CD3 ε subunit also contains a proline-rich sequence and a basic-rich stretch (BRS). The CD3 ε BRS complexes selected phosphoinositides, interactions that are required for normal cell surface expression of the TCR. The cytoplasmic domain of CD3 ζ also contains several clusters of arginine and lysine residues. In this study, we report that these basic amino acids enable CD3 ζ to complex the phosphoinositides PtdIns(3)P, PtdIns(4)P, PtdIns(5)P, PtdIns(3,5)P(2), and PtdIns(3,4,5)P(3) with high affinity. Early TCR signaling pathways were unaffected by the targeted loss of the phosphoinositide-binding functions of CD3 ζ. Instead, the elimination of the phosphoinositide-binding function of CD3 ζ significantly impaired the ability of this invariant chain to accumulate stably at the immunological synapse during T cell-APC interactions. Without its phosphoinositide-binding functions, CD3 ζ was concentrated in intracellular structures after T cell activation. Such findings demonstrate a novel functional role for CD3 ζ BRS-phosphoinositide interactions in supporting T cell activation.
authors.affiliation: Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeFord-Watts
authors.forename: David S
authors.initials: DS
authors.lastname: Dougall
authors.forename: Serkan
authors.initials: S
authors.lastname: Belkaya
authors.forename: Blake A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Eitson
authors.forename: Kole T
authors.initials: KT
authors.lastname: Roybal
authors.forename: Barbara
authors.initials: B
authors.lastname: Barylko
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Albanesi
authors.forename: Christoph
authors.initials: C
authors.lastname: Wülfing
authors.forename: Nicolai S C
authors.initials: NS
authors.lastname: van Oers
mesh_terms: D024361:Amino Acids, Basic; D000818:Animals; D001665:Binding Sites / Q000276:immunology; D017252:CD3 Complex / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D054992:Immunological Synapses; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010716:Phosphatidylinositols / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014162:Transfection
chemical_list: D024361:Amino Acids, Basic; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D010716:Phosphatidylinositols; D017260:Receptor-CD3 Complex, Antigen, T-Cell