title: Naturally occurring low affinity peptide/MHC class I ligands can mediate negative selection and T cell activation.
abstract: The affinity/avidity model for T cell development postulates that ligands with high affinity for the TCR are efficient in negative selection, whereas those with lower affinity/avidity favor positive selection. Using the 2C TCR transgenic model, we evaluated the efficacy of ligands with widely differing affinity for the TCR (3 x 10(3) to 2 x 10(6) M(-1)) in mediating thymocyte deletion. The relative affinities of the 2C TCR for the p2Ca/Ld, dEV-8/Kb, p2Ca-A3/Ld, and p2Ca/Kb ligands are approximately 1000:50:10:1, respectively. Here we show, using an in vitro assay, that the deletion of 2C CD4+ CD8+ thymocytes is mediated not only by p2Ca/Ld, but also by the lower affinity ligands dEV-8/Kb, p2Ca-A3/Ld, and p2Ca/Kb, albeit at relatively higher peptide concentrations. Deletion mediated by low affinity ligands required CD8, whereas high affinity ligand-mediated deletion was CD8 independent. The p2Ca/Kb and dEV-8/Kb ligands are naturally occurring in H-2b mice, and others have shown that p2Ca/Kb can induce the maturation of CD4- CD8+ 2C-TCR(high) thymocytes in fetal thymic organ culture. In this study we showed that in addition to deletion, the p2Ca/Kb and dEV-8/Kb ligands, in the presence of exogenous IL-2, induced mature 2C T cell proliferation, albeit at a lower level than that induced by the high affinity p2Ca/Ld ligand. Thus, the same low affinity ligands that can effect negative selection and, in the case of p2Ca/Kb, the maturation of CD8 single-positive thymocytes can also induce the activation of mature CD8 T cells.
authors.affiliation: Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Motyka
authors.forename: H S
authors.initials: HS
authors.lastname: Teh
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D017637:Clonal Deletion; D004306:Dose-Response Relationship, Immunologic; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D001613:beta 2-Microglobulin / Q000172:deficiency
chemical_list: D015395:Histocompatibility Antigens Class I; D008024:Ligands; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D001613:beta 2-Microglobulin