RAG-dependent peripheral T cell receptor diversification in CD8+ T lymphocytes.
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.
Serra
Pau
P
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.
Amrani
Abdelaziz
A
Han
Bingye
B
Yamanouchi
Jun
J
Thiessen
Shari J
SJ
Santamaria
Pere
P
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
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