Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity

Immunity. 2001 Dec;15(6):959-70. doi: 10.1016/s1074-7613(01)00254-0.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Autoimmune Diseases / genetics*
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • Autoimmunity / genetics
  • Autoimmunity / immunology*
  • Cell Cycle Proteins*
  • Cell Division
  • Chimera
  • Clonal Deletion
  • DNA-Binding Proteins*
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F2 Transcription Factor
  • Gene Expression Regulation / immunology*
  • Glomerulonephritis, Membranoproliferative / genetics
  • Glomerulonephritis, Membranoproliferative / immunology
  • H-Y Antigen / genetics
  • H-Y Antigen / immunology
  • Humans
  • Immunologic Memory
  • Inflammation
  • Jurkat Cells
  • Lymphocyte Activation
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutagenesis, Site-Directed
  • Receptors, Antigen, T-Cell / immunology
  • Recombinant Fusion Proteins / immunology
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology*
  • S Phase / genetics
  • Self Tolerance / genetics
  • Self Tolerance / immunology*
  • Splenomegaly / genetics
  • Splenomegaly / immunology
  • T-Lymphocytes / cytology*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Thymus Gland / immunology
  • Thymus Gland / pathology
  • Transcription Factors / biosynthesis
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transfection

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • E2F Transcription Factors
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • E2F2 Transcription Factor
  • E2F2 protein, human
  • E2f1 protein, mouse
  • H-Y Antigen
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • Repressor Proteins
  • Transcription Factors