title: Kinetics of T-cell receptor binding by bivalent HLA-DR. Peptide complexes that activate antigen-specific human T-cells.
abstract: Monovalent major histocompatibility complex-peptide complexes dissociate within seconds from the T-cell receptor (TCR), indicating that dimerization/multimerization may be important during early stages of T-cell activation. Soluble bivalent HLA-DR2.myelin basic protein (MBP) peptide complexes were expressed by replacing the F(ab) arms of an IgG2a antibody with HLA-DR2.MBP peptide complexes. The binding of bivalent HLA-DR2.peptide complexes to recombinant TCR was examined by surface plasmon resonance. The bivalent nature greatly enhanced TCR binding and slowed dissociation from the TCR, with a t((1)/(2)) of 2.1 to 4.6 min. Soluble bivalent HLA-DR2.MBP peptide complexes activated antigen-specific T-cells in the absence of antigen presenting cells. In contrast, soluble antibodies to the TCR.CD3 complex were ineffective, indicating that they failed to induce an active TCR dimer. TCR/CD3 antibodies induced T-cell proliferation when bound by antigen presenting cells that expressed Fc receptors. In the presence of dendritic cells, bivalent HLA-DR2. MBP peptide complexes induced T-cell activation at >100-fold lower concentrations than TCR/CD3 antibodies and were also superior to peptide or antigen. These results demonstrate that bivalent HLA-DR. peptide complexes represent effective ligands for activation of the TCR. The data support a role for TCR dimerization in early TCR signaling and kinetic proofreading.
authors.affiliation: Department of Cancer Immunology & AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: H
authors.initials: H
authors.lastname: Appel
authors.forename: L
authors.initials: L
authors.lastname: Gauthier
authors.forename: J
authors.initials: J
authors.lastname: Pyrdol
authors.forename: K W
authors.initials: KW
authors.lastname: Wucherpfennig
mesh_terms: D017252:CD3 Complex / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D015802:HLA-DR2 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D004676:Myelin Basic Protein / Q000276:immunology* / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D015802:HLA-DR2 Antigen; D004676:Myelin Basic Protein; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins