title: The ability to rearrange dual TCRs enhances positive selection, leading to increased Allo- and Autoreactive T cell repertoires.
abstract: Thymic selection is designed to ensure TCR reactivity to foreign Ags presented by self-MHC while minimizing reactivity to self-Ags. We hypothesized that the repertoire of T cells with unwanted specificities such as alloreactivity or autoreactivity are a consequence of simultaneous rearrangement of both TCRα loci. We hypothesized that this process helps maximize production of thymocytes capable of successfully completing thymic selection, but results in secondary TCRs that escape stringent selection. In T cells expressing two TCRs, one TCR can mediate positive selection and mask secondary TCR from negative selection. Examination of mice heterozygous for TRAC (TCRα(+/-)), capable of only one functional TCRα rearrangement, demonstrated a defect in generating mature T cells attributable to decreased positive selection. Elimination of secondary TCRs did not broadly alter the peripheral T cell compartment, though deep sequencing of TCRα repertoires of dual TCR T cells and TCRα(+/-) T cells demonstrated unique TCRs in the presence of secondary rearrangements. The functional impact of secondary TCRs on the naive peripheral repertoire was evidenced by reduced frequencies of T cells responding to autoantigen and alloantigen peptide-MHC tetramers in TCRα(+/-) mice. T cell populations with secondary TCRs had significantly increased ability to respond to altered peptide ligands related to their allogeneic ligand as compared with TCRα(+/-) cells, suggesting increased breadth in peptide recognition may be a mechanism for their reactivity. Our results imply that the role of secondary TCRs in forming the T cell repertoire is perhaps more significant than what has been assumed.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ni
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Solomon
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110; and.
authors.forename: Chyi-Song
authors.initials: CS
authors.lastname: Hsieh
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Paul M
authors.initials: PM
authors.lastname: Allen
authors.affiliation: Department of Pathology, University of California, San Diego, La Jolla, CA 92093 gpmorris@ucsd.edu.
authors.forename: Gerald P
authors.initials: GP
authors.lastname: Morris
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016466:CHO Cells; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003412:Cricetulus; D014644:Genetic Variation; D006086:Graft vs Host Disease / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics* / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D060168:Thymocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D016693:Receptors, Antigen, T-Cell, alpha-beta