title: Differential signaling and hierarchical response thresholds induced by an immunodominant peptide of myelin basic protein and an altered peptide ligand in human T cells.
abstract: Changes in peptide antigen concentration or structure can have a profound effect on T cell responsiveness by inducing selected T cell effector functions. In this study, we have compared the biological responses of an MBP83-99-specific human Th0 T cell clone (TCC) stimulated with increasing concentrations of native peptide or an altered peptide ligand (APL). Our results show that the hierarchy of response thresholds for proliferation and cytokine secretion is similar for native peptide and APL. However, because a much higher concentration of the APL is required to evoke the same degree of response, the cytokine profile is shifted towards a Th2-like response relative to the same concentration of native peptide. In addition, we observed qualitative differences in TCR signal transduction triggered by native peptide and a weak agonist APL even at concentrations that elicit similar biological responses. Thus, the relationship between TCR signaling and biological responses may be more complex than previously recognized.
authors.affiliation: Neurocrine Biosciences, Inc., San Diego, CA 92121, USA. pcrowe@neurocrine.com
authors.forename: P D
authors.initials: PD
authors.lastname: Crowe
authors.forename: S A
authors.initials: SA
authors.lastname: Boehme
authors.forename: T
authors.initials: T
authors.lastname: Wong
authors.forename: A
authors.initials: A
authors.lastname: Gaur
authors.forename: J
authors.initials: J
authors.lastname: Sidney
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: P J
authors.initials: PJ
authors.lastname: Conlon
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001402:B-Lymphocytes; D001665:Binding Sites; D002455:Cell Division; D002460:Cell Line; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D051380:GRB2 Adaptor Protein; D006684:HLA-DR Antigens / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006801:Humans; D016056:Immunodominant Epitopes; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000737:chemistry / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D051746:ZAP-70 Protein-Tyrosine Kinase; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D016056:Immunodominant Epitopes; D008565:Membrane Proteins; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain; C104448:myelin basic protein 83-99; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019061:src-Family Kinases