       Document 0045
 DOCN  M9580045
 TI    Differential activation of proliferation and cytotoxicity in human
       T-cell lymphotropic virus type I Tax-specific CD8 T cells by an altered
       peptide ligand.
 DT    9506
 AU    Hollsberg P; Weber WE; Dangond F; Batra V; Sette A; Hafler DA;
       Laboratory of Molecular Immunology, Brigham & Women's Hospital,; Boston,
       MA, USA.
 SO    Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):4036-40. Unique Identifier :
       AIDSLINE MED/95249607
 AB    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.
 DE    Amino Acid Sequence  B-Lymphocytes/*IMMUNOLOGY  Binding Sites  Cell
       Division  Cell Line, Transformed  *Cytotoxicity, Immunologic
       CD8-Positive T-Lymphocytes/*IMMUNOLOGY/*VIROLOGY  Gene Products,
       tax/*IMMUNOLOGY  Herpesvirus 4, Human/IMMUNOLOGY  Human  HLA-A2
       Antigen/METABOLISM  HTLV-I/*IMMUNOLOGY  Kinetics  *Lymphocyte
       Transformation  Molecular Sequence Data  Mutagenesis, Site-Directed
       Point Mutation  Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.
       Thymidine/METABOLISM  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

