title: Low-avidity self-specific T cells display a pronounced expansion defect that can be overcome by altered peptide ligands.
abstract: Thymic expression of self-Ags results in the deletion of high-avidity self-specific T cells, but, at least for certain Ags, a residual population of self-specific T cells with low-affinity TCRs remains after negative selection. Such self-specific T cells are thought to play a role in the induction of T cell-mediated autoimmunity, but may also be used for the induction of antitumor immunity against self-Ags. In this study, we examine the functional competence of a polyclonal population of self-specific CD8+ T cells. We show that low-affinity interactions between TCR and peptide are associated with selective loss of critical T cell functions. Triggering of low levels of IFN-gamma production and cytolytic activity through low-affinity TCRs readily occurs provided high Ag doses are used, but IL-2 production and clonal expansion are severely reduced at all Ag doses. Remarkably, a single peptide variant can form an improved ligand for the highly diverse population of low-avidity self-specific T cells and can improve their proliferative capacity. These data provide insight into the inherent limitations of self-specific T cell responses through low-avidity TCR signals and the effect of modified peptide ligands on self-specific T cell immunity.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: K E
authors.initials: KE
authors.lastname: de Visser
authors.forename: T A
authors.initials: TA
authors.lastname: Cordaro
authors.forename: H W
authors.initials: HW
authors.lastname: Kessels
authors.forename: F H
authors.initials: FH
authors.lastname: Tirion
authors.forename: T N
authors.initials: TN
authors.lastname: Schumacher
authors.forename: A M
authors.initials: AM
authors.lastname: Kruisbeek
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003601:Cytotoxicity Tests, Immunologic; D007700:Kinetics; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D010455:Peptides / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D001324:Autoantigens; D016207:Cytokines; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D014758:Viral Core Proteins; C102366:nucleoprotein (366-374), influenza virus