title: T cell-specific inhibition of multiple apoptotic pathways blocks negative selection and causes autoimmunity.
abstract: T cell self-tolerance is thought to involve peripheral tolerance and negative selection, involving apoptosis of autoreactive thymocytes. However, evidence supporting an essential role for negative selection is limited. Loss of Bim, a Bcl-2 BH3-only protein essential for thymocyte apoptosis, rarely results in autoimmunity on the C57BL/6 background. Mice with T cell-specific over-expression of Bcl-2, that blocks multiple BH3-only proteins, are also largely normal. The nuclear receptor Nur77, also implicated in negative selection, might function redundantly to promote apoptosis by associating with Bcl-2 and exposing its potentially pro-apoptotic BH3 domain. Here, we report that T cell-specific expression of a Bcl2 BH3 mutant transgene results in enhanced rescue of thymocytes from negative selection. Concomitantly, Treg development is increased. However, aged BH3 mutant mice progressively accumulate activated, autoreactive T cells, culminating in development of multi-organ autoimmunity and lethality. These data provide strong evidence that negative selection is crucial for establishing T cell tolerance.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Burger
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Leung
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Margaux J
authors.initials: MJ
authors.lastname: Bennett
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.
authors.forename: Astar
authors.initials: A
authors.lastname: Winoto
mesh_terms: D000483:Alleles; D000818:Animals; D000941:Antigens / Q000737:chemistry; D017209:Apoptosis; D015551:Autoimmunity / Q000276:immunology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000276:immunology; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology*; D060168:Thymocytes / Q000378:metabolism; D013950:Thymus Gland / Q000378:metabolism; D019076:Transgenes
chemical_list: D000941:Antigens; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1
keywords: Bcl-2; Nur77; T cell tolerance; autoimmunity; immunology; mouse; negative selection