title: Differential activation of proliferation and cytotoxicity in human T-cell lymphotropic virus type I Tax-specific CD8 T cells by an altered peptide ligand.
abstract: Human T-cell leukemia virus type I (HTLV-I) gives rise to a neurologic disease known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the pathogenesis of the disease is unknown, the presence of a remarkably high frequency of Tax-specific, cytotoxic CD8 T cells may suggest a role of these cells in the development of HAM/TSP. Antigen-mediated signaling in a CD8 T-cell clone specific for the Tax(11-19) peptide of HTLV-I was studied using analog peptides substituted in their T-cell receptor contact residues defined by x-ray crystallographic data of the Tax(11-19) peptide in the groove of HLA-A2. CD8 T-cell stimulation with the wild-type peptide antigen led to activation of p56lck kinase activity, interleukin 2 secretion, cytotoxicity, and clonal expansion. A Tax analog peptide with an alanine substitution of the T-cell receptor contact residue tyrosine-15 induced T-cell-mediated cytolysis without activation of interleukin 2 secretion or proliferation. Induction of p56lck kinase activity correlated with T-cell-mediated cytotoxicity, whereas interleukin 2 secretion correlated with [3H]thymidine incorporation and proliferation. Moreover, Tax peptide analogs that activated the tyrosine kinase activity of p56lck could induce unresponsiveness to secondary stimulation with the wild-type peptide. These observations show that a single amino acid substitution in a T-cell receptor contact residue of Tax can differentially signal CD8 T cells and further demonstrate that primary activation has functional consequences for the secondary response of at least some Tax-specific CD8 T cells to HTLV-I-infected target cells.
authors.affiliation: Laboratory of Molecular Immunology, Brigham & Women's Hospital, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Höllsberg
authors.forename: W E
authors.initials: WE
authors.lastname: Weber
authors.forename: F
authors.initials: F
authors.lastname: Dangond
authors.forename: V
authors.initials: V
authors.lastname: Batra
authors.forename: A
authors.initials: A
authors.lastname: Sette
authors.forename: D A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000595:Amino Acid Sequence; D001402:B-Lymphocytes / Q000276:immunology*; D001665:Binding Sites; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology*; D002455:Cell Division; D002461:Cell Line, Transformed; D003602:Cytotoxicity, Immunologic; D016356:Gene Products, tax / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000276:immunology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D013936:Thymidine / Q000378:metabolism
chemical_list: D016356:Gene Products, tax; D015789:HLA-A2 Antigen; D013936:Thymidine