title: Bcl-2-interacting mediator of cell death influences autoantigen-driven deletion and TCR revision.
abstract: Peripheral CD4(+)Vβ5(+) T cells are tolerized to an endogenous mouse mammary tumor virus superantigen either by deletion or TCR revision. Through TCR revision, RAG reexpression mediates extrathymic TCRβ rearrangement and results in a population of postrevision CD4(+)Vβ5(-) T cells expressing revised TCRβ chains. We have hypothesized that cell death pathways regulate the selection of cells undergoing TCR revision to ensure the safety and utility of the postrevision population. In this study, we investigate the role of Bcl-2-interacting mediator of cell death (Bim)-mediated cell death in autoantigen-driven deletion and TCR revision. Bim deficiency and Bcl-2 overexpression in Vβ5 transgenic (Tg) mice both impair peripheral deletion. Vβ5 Tg Bim-deficient and Bcl-2 Tg mice exhibit an elevated frequency of CD4(+) T cells expressing both the transgene-encoded Vβ5 chain and a revised TCRβ chain. We now show that these dual-TCR-expressing cells are TCR revision intermediates and that the population of RAG-expressing, revising CD4(+) T cells is increased in Bim-deficient Vβ5 Tg mice. These findings support a role for Bim and Bcl-2 in regulating the balance of survival versus apoptosis in peripheral T cells undergoing RAG-dependent TCR rearrangements during TCR revision, thereby ensuring the utility of the postrevision repertoire.
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98195, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Hale
authors.forename: Lisa T
authors.initials: LT
authors.lastname: Nelson
authors.forename: Kalynn B
authors.initials: KB
authors.lastname: Simmons
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Fink
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D001324:Autoantigens / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D015329:Gene Rearrangement, T-Lymphocyte / Q000276:immunology; D016654:Genes, RAG-1 / Q000276:immunology; D006801:Humans; D008212:Lymphocyte Depletion; D008324:Mammary Tumor Virus, Mouse / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D001324:Autoantigens; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell