title: RAG-dependent peripheral T cell receptor diversification in CD8+ T lymphocytes.
abstract: Rearrangement of T cell receptor (TCR) genes is driven by transient expression of V(D)J recombination-activating genes (RAGs) during lymphocyte development. Immunological dogma holds that T cells irreversibly terminate RAG expression before exiting the thymus, and that all of the progeny arising from mature T cells express the parental TCRs. When single pancreatic islet-derived, NRP-A7 peptide-reactive CD8(+) T cells from nonobese diabetic (NOD) mice were repeatedly stimulated with peptide-pulsed dendritic cells, daughter T cells reexpressed RAGs, lost their ability to bind to NRP-A7K(d) tetramers, ceased to transcribe tetramer-specific TCR genes, and, instead, expressed a vast array of other TCR rearrangements. Pancreatic lymph node (PLN) CD8(+) T cells from animals expressing a transgenic NRP-A7-reactive TCR transcribed and translated RAGs in vivo and displayed endogenous TCRs on their surface. RAG reexpression also occurred in the PLN CD8(+) T cells of wild-type NOD mice and could be induced in the peripheral CD8(+) T cells of nondiabetes-prone TCR-transgenic B10.H2(g7) mice by stimulation with peptide-pulsed dendritic cells. In contrast, reexpression of RAGs could not be induced in the CD8(+) T cells of B6 mice expressing an ovalbumin-specific, K(b)-restricted TCR, or in the CD8(+) T cells of NOD mice expressing a lymphocytic choriomeningitis virus-specific, D(b)-restricted TCR. Extra-thymic reexpression of the V(D)J recombination machinery in certain CD8(+) T cell subpopulations, therefore, enables further diversification of the peripheral T cell repertoire.
authors.affiliation: Department of Microbiology and Infectious Diseases, and Julia McFarlane Diabetes Research Centre, Faculty of Medicine, Health Sciences Centre, University of Calgary, 3330 Hospital Drive N.W., AB, Canada T2N 4N1.
authors.forename: Pau
authors.initials: P
authors.lastname: Serra
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Amrani
authors.forename: Bingye
authors.initials: B
authors.lastname: Han
authors.forename: Jun
authors.initials: J
authors.lastname: Yamanouchi
authors.forename: Shari J
authors.initials: SJ
authors.lastname: Thiessen
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000941:Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002999:Clone Cells / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D016654:Genes, RAG-1; D006183:H-2 Antigens / Q000276:immunology; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D000941:Antigens; D004268:DNA-Binding Proteins; D006183:H-2 Antigens; C024755:H-2K(K) antigen; D018398:Homeodomain Proteins; D010446:Peptide Fragments; C499308:Rag2 protein, mouse; D016693:Receptors, Antigen, T-Cell, alpha-beta; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D010047:Ovalbumin