A kinetic threshold between negative and positive selection based on the longevity of the T cell receptor-ligand complex.
We have developed a unique in vivo system to determine the relationship between endogenous altered peptide ligands and the development of major histocompatibility complex class II- restricted T cells. Our studies use the 3.L2 T cell receptor (TCR) transgenic mouse, in which T cells are specific for Hb(64-76)/I-Ek and positively selected on I-Ek plus self-peptides. To this endogenous peptide repertoire, we have individually added one of six well-characterized 3.L2 ligands. This transgenic approach expands rather than constrains the repertoire of self-peptides. We find that a broad range of ligands produce negative selection of thymocytes in vivo. When compared with the in vitro TCR-ligand binding kinetics, we find that these negatively selecting ligands all have a half-life of 2 s or greater. Additionally, one of two ligands examined with no detectable binding to the 3.L2 TCR and no activity on mature 3.L2 T cells (Q72) enhances the positive selection of transgenic thymocytes in vivo. Together, these data establish a kinetic threshold between negative and positive selection based on the longevity of TCR-ligand complexes.
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D006454:Hemoglobins / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006825:Hybridomas / Q000276:immunology; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000276:immunology