title: Weak agonist self-peptides promote selection and tuning of virus-specific T cells.
abstract: Recent progress has begun to define the interactions and signaling pathways that are triggered during positive selection. To identify and further examine self-peptides that can mediate positive selection, we searched a protein-database to find peptides that have minimal homology with the viral peptide (p33) that activates a defined P14 transgenic TCR. We identified four peptides that could bind the restriction element H-2D(b) and induce proliferation of P14 transgenic splenocytes at high concentration. Two of the four peptides (DBM and RPP) were able to positively select the virus-specific TCR in fetal thymic organ culture but were unable to induce clonal deletion. Reverse-phase HPLC and mass spectrometry demonstrated that these peptides were presented by H-2D(b) molecules on thymic epithelial cell lines. We also examined whether the selecting ligands altered T cell responsiveness in vitro. DBM-selected T cells lost their ability to respond to the positively selecting ligand DBM, whereas RPP-selected T cells only retained their ability to respond to high concentrations of RPP. These results demonstrate that self-peptides that mediate positive selection can differentially "tune" the activation threshold of T cells and alter the functional repertoire of T cells.
authors.affiliation: Departments of Medical Biophysics and Immunology, University Health Network, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Saibil
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ohteki
authors.forename: Forest M
authors.initials: FM
authors.lastname: White
authors.forename: Mark
authors.initials: M
authors.lastname: Luscher
authors.forename: Arsen
authors.initials: A
authors.lastname: Zakarian
authors.forename: Alisha
authors.initials: A
authors.lastname: Elford
authors.forename: Jeffery
authors.initials: J
authors.lastname: Shabanowitz
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.forename: Patrice
authors.initials: P
authors.lastname: Hugo
authors.forename: Josef
authors.initials: J
authors.lastname: Penninger
authors.forename: Brian
authors.initials: B
authors.lastname: Barber
authors.forename: Donald F
authors.initials: DF
authors.lastname: Hunt
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Ohashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004299:Dopamine beta-Hydroxylase / Q000276:immunology; D066246:ErbB Receptors / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D064532:Histocompatibility Antigen H-2D; D008213:Lymphocyte Activation; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D004299:Dopamine beta-Hydroxylase; D066246:ErbB Receptors