title: Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity.
abstract: E2Fs are important regulators of proliferation, differentiation, and apoptosis. Here we characterize the phenotype of mice deficient in E2F2. We show that E2F2 is required for immunologic self-tolerance. E2F2(-/-) mice develop late-onset autoimmune features, characterized by widespread inflammatory infiltrates, glomerular immunocomplex deposition, and anti-nuclear antibodies. E2F2-deficient T lymphocytes exhibit enhanced TCR-stimulated proliferation and a lower activation threshold, leading to the accumulation of a population of autoreactive effector/memory T lymphocytes, which appear to be responsible for causing autoimmunity in E2F2-deficient mice. Finally, we provide support for a model to explain E2F2's unexpected role as a suppressor of T lymphocyte proliferation. Rather than functioning as a transcriptional activator, E2F2 appears to function as a transcriptional repressor of genes required for normal S phase entry, particularly E2F1.
authors.affiliation: Department of Animal Biology and Genetics, Faculty of Sciences, University of the Basque Country, Bilbao, E-48080, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Murga
authors.forename: O
authors.initials: O
authors.lastname: Fernández-Capetillo
authors.forename: S J
authors.initials: SJ
authors.lastname: Field
authors.forename: B
authors.initials: B
authors.lastname: Moreno
authors.forename: L R
authors.initials: LR
authors.lastname: Borlado
authors.forename: Y
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: D
authors.initials: D
authors.lastname: Balomenos
authors.forename: A
authors.initials: A
authors.lastname: Vicario
authors.forename: A C
authors.initials: AC
authors.lastname: Carrera
authors.forename: S H
authors.initials: SH
authors.lastname: Orkin
authors.forename: M E
authors.initials: ME
authors.lastname: Greenberg
authors.forename: A M
authors.initials: AM
authors.lastname: Zubiaga
mesh_terms: D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D018797:Cell Cycle Proteins; D002455:Cell Division; D002678:Chimera; D017637:Clonal Deletion; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; D005786:Gene Expression Regulation / Q000276:immunology*; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics / Q000276:immunology; D006182:H-Y Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007249:Inflammation; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D016196:S Phase / Q000235:genetics; D017634:Self Tolerance / Q000235:genetics / Q000276:immunology*; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D050703:E2F2 Transcription Factor; C493761:E2F2 protein, human; C493754:E2f1 protein, mouse; D006182:H-Y Antigen; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D014157:Transcription Factors