title: T cell tolerance based on avidity thresholds rather than complete deletion allows maintenance of maximal repertoire diversity.
abstract: Given the flexible nature of TCR specificity, deletion or permanent disabling of all T cells with the capacity to recognize self peptides would severely limit the diversity of the repertoire and the capacity to recognize foreign Ags. To address this, we have investigated the patterns of CD8+ CTL reactivity to a naturally H-2Kb-presented self peptide derived from the elongation factor 1alpha (EF1alpha). EF1alpha occurs as two differentially expressed isoforms differing at one position of the relevant peptide. Low avidity CTLs could be raised against both variants of the EF1alpha peptide. These CTLs required 100-fold more peptide-H-2Kb complexes on the target cell compared with CTLs against a viral peptide, and did not recognize the naturally expressed levels of EF1alpha peptides. Thus, low avidity T cells specific for these self peptides escape tolerance by deletion, despite expression of both EF1alpha isoforms in dendritic cells known to mediate negative selection in the thymus. The low avidity in CTL recognition of these peptides correlated with low TCR affinity. However, self peptide-specific CTLs expressed elevated levels of CD8. Furthermore, CTLs generated against altered self peptide variants displayed intermediate avidity, indicating cross-reactivity in induction of tolerance. We interpret these data, together with results previously published by others, in an avidity pit model based on avidity thresholds for maintenance of both maximal diversity and optimal self tolerance in the CD8+ T cell repertoire.
authors.affiliation: Microbiology and Tumor Biology Center and Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. jsandber@adarc.adarc.org
authors.forename: J K
authors.initials: JK
authors.lastname: Sandberg
authors.forename: L
authors.initials: L
authors.lastname: Franksson
authors.forename: J
authors.initials: J
authors.lastname: Sundbäck
authors.forename: J
authors.initials: J
authors.lastname: Michaelsson
authors.forename: M
authors.initials: M
authors.lastname: Petersson
authors.forename: A
authors.initials: A
authors.lastname: Achour
authors.forename: R P
authors.initials: RP
authors.lastname: Wallin
authors.forename: N E
authors.initials: NE
authors.lastname: Sherman
authors.forename: T
authors.initials: T
authors.lastname: Bergman
authors.forename: H
authors.initials: H
authors.lastname: Jörnvall
authors.forename: D F
authors.initials: DF
authors.lastname: Hunt
authors.forename: R
authors.initials: R
authors.lastname: Kiessling
authors.forename: K
authors.initials: K
authors.lastname: Kärre
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D017637:Clonal Deletion; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D006183:H-2 Antigens / Q000276:immunology* / Q000378:metabolism*; D007108:Immune Tolerance; D008221:Lymphoid Tissue / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009842:Oligopeptides / Q000096:biosynthesis / Q000276:immunology / Q000302:isolation & purification / Q000378:metabolism; D020648:Peptide Elongation Factor 1 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D020033:Protein Isoforms / Q000096:biosynthesis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020539:Sequence Analysis, Protein; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D016827:CD8 Antigens; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D009842:Oligopeptides; D020648:Peptide Elongation Factor 1; D020033:Protein Isoforms; D011948:Receptors, Antigen, T-Cell