Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity.
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.
Murga
M
M
Department of Animal Biology and Genetics, Faculty of Sciences, University of the Basque Country, Bilbao, E-48080, Spain.
Fernández-Capetillo
O
O
Field
S J
SJ
Moreno
B
B
Borlado
L R
LR
Fujiwara
Y
Y
Balomenos
D
D
Vicario
A
A
Carrera
A C
AC
Orkin
S H
SH
Greenberg
M E
ME
Zubiaga
A M
AM
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
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