title: A physiological ligand of positive selection is recognized as a weak agonist.
abstract: Positive selection is a process that ensures that peripheral T cells express TCR that are self-MHC restricted. This process occurs in the thymus and requires both self-MHC and self-peptides. We have recently established a TCR transgenic (TCR(trans)(+)) mouse model using the C10.4 TCR restricted to the MHC class Ib molecule, H2-M3. Having defined H2-M3 as the positively selecting MHC molecule, the severely limited number of H2-M3 binding peptides allowed us to characterize a mitochondrial NADH dehydrogenase subunit 1-derived 9-mer peptide as the physiological ligand of positive selection. Here, we demonstrate that the NADH dehydrogenase subunit 1 self-peptide is seen by mature C10.4 TCR(trans)(+) T cells as a weak agonist and induces positive selection at a defined concentration range. We also found that the full-length cognate peptide, a strong agonist for mature C10.4 TCR(trans)(+) T cells, initiated positive selection, albeit at significantly lower concentrations. At increased peptide concentrations, and thus increased epitope densities, either peptide only induced the development of partially functional T cells. We conclude that successful positive selection only proceeded at a defined, yet fairly narrow window of avidity.
authors.affiliation: Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Berg
authors.forename: S
authors.initials: S
authors.lastname: Irion
authors.forename: S
authors.initials: S
authors.lastname: Kattman
authors.forename: M F
authors.initials: MF
authors.lastname: Princiotta
authors.forename: U D
authors.initials: UD
authors.lastname: Staerz
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D004306:Dose-Response Relationship, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009245:NADH Dehydrogenase / Q000276:immunology / Q000378:metabolism; D009842:Oligopeptides / Q000819:agonists* / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D009924:Organ Culture Techniques; D011948:Receptors, Antigen, T-Cell / Q000819:agonists* / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D019076:Transgenes / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: C078177:H2-M3 antigen; D015395:Histocompatibility Antigens Class I; D008024:Ligands; D009842:Oligopeptides; D011948:Receptors, Antigen, T-Cell; D009245:NADH Dehydrogenase