title: Unique T cell proliferation associated with PKCmu activation and impaired ZAP-70 phosphorylation in recognition of overexpressed HLA/partially agonistic peptide complexes.
abstract: Altered peptide ligands (APL) induce T cell responses different from those induced by the original agonistic peptide. As shown for CD4(+) T cells, partial agonists induce partial T cell activation without proliferation because of lower affinities and higher off rates to TCR than those of agonists. To determine whether overexpression of partially agonistic TCR ligands on antigen-presenting cells provides high-avidity TCR ligands, we generated L cell transfectants expressing various numbers of HLA-DR4 covalently linked with APL derived from a streptococcal peptide and observed responses of the cognate T cells. Some overexpressed HLA-DR4/partially agonistic APL complexes induced T cell proliferation in a density-dependent manner. However, tyrosine phosphorylation of zeta-associated protein-70 (ZAP-70) and linker for activation of T cells and kinase activity of ZAP-70 were not detectable. T cell proliferation stimulated with L cell transfectants was sensitive to the PKC inhibitor Gö6976, but to a lesser extent to Gö6983, suggesting the involvement of mu isotype of PKC (PKCmu). In vitro kinase assays revealed that PKCmu activity was up-regulated only in T cells stimulated with L cell transfectants that induced T cell proliferation. Our data suggest the presence of a unique signaling pathway coupling TCR ligation with T cell proliferation associated with PKCmu activation and impaired ZAP-70 activation.
authors.affiliation: Division of Immunogenetics, Department of Neuroscience and Immunology, Kumamoto University Graduate School of Medical Sciences, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.forename: Yu-Zhen
authors.initials: YZ
authors.lastname: Chen
authors.forename: Hirotake
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: Toko
authors.initials: T
authors.lastname: Jotsuka
authors.forename: Masako
authors.initials: M
authors.lastname: Masuda
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D001457:Anion Exchange Protein 1, Erythrocyte / Q000235:genetics / Q000378:metabolism; D017951:Antigen Presentation / Q000502:physiology*; D000942:Antigens, Bacterial / Q000276:immunology*; D001425:Bacterial Outer Membrane Proteins / Q000737:chemistry / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D002227:Carbazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured / Q000201:enzymology / Q000276:immunology; D018920:Coculture Techniques; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015804:HLA-DR4 Antigen / Q000276:immunology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D007739:L Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology*; D014162:Transfection; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001457:Anion Exchange Protein 1, Erythrocyte; D000942:Antigens, Bacterial; D001425:Bacterial Outer Membrane Proteins; D002227:Carbazoles; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D015804:HLA-DR4 Antigen; D007211:Indoles; C110810:LAT protein, human; C491734:Lat protein, mouse; D008024:Ligands; D008565:Membrane Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C014689:streptococcal M protein; C081021:Go 6976; C089212:protein kinase D; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse; D011493:Protein Kinase C; C064758:Ro 31-8220