title: CD4 enhances T cell sensitivity to antigen by coordinating Lck accumulation at the immunological synapse.
abstract: How T cells respond with extraordinary sensitivity to minute amounts of agonist peptide and major histocompatibility complex (pMHC) molecules on the surface of antigen-presenting cells bearing large numbers of endogenous pMHC molecules is not understood. Here we present evidence that CD4 affects the responsiveness of T helper cells by controlling spatial localization of the tyrosine kinase Lck in the synapse. This finding, as well as further in silico and in vitro experiments, led us to develop a molecular model in which endogenous and agonist pMHC molecules act cooperatively to amplify T cell receptor signaling. At the same time, activation due to endogenous pMHC molecules alone is inhibited. A key feature is that the binding of agonist pMHC molecules to the T cell receptor results in CD4-mediated spatial localization of Lck, which in turn enables endogenous pMHC molecules to trigger many T cell receptors. We also discuss broader implications for T cell biology, including thymic selection, diversity of the repertoire of self pMHC molecules and serial triggering.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Dinner
authors.forename: Shuyan
authors.initials: S
authors.lastname: Qi
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
authors.forename: Johannes B
authors.initials: JB
authors.lastname: Huppa
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.forename: Arup K
authors.initials: AK
authors.lastname: Chakraborty
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D003198:Computer Simulation; D007091:Image Processing, Computer-Assisted; D008213:Lymphocyte Activation / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology*; D008285:Major Histocompatibility Complex; D051379:Mice; D018448:Models, Immunological; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*
chemical_list: D000941:Antigens; D015704:CD4 Antigens; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)