Epigenetic modifications induced by Blimp-1 Regulate CD8⁺ T cell memory progression during acute virus infection

Immunity. 2013 Oct 17;39(4):661-75. doi: 10.1016/j.immuni.2013.08.032. Epub 2013 Oct 10.

Abstract

The transcription factor Blimp-1 regulates the overall accumulation of virus-specific CD8⁺ T cells during acute viral infections. We found that increased proliferation and survival of Blimp-1-deficient CD8⁺ T cells resulted from sustained expression of CD25 and CD27 and persistent cytokine responsiveness. Silencing of Il2ra and Cd27 reduced the Blimp-1-deficient CD8⁺ T cell response. Genome-wide chromatin immunoprecipitation (ChIP) sequencing analysis identified Il2ra and Cd27 as direct targets of Blimp-1. At the peak of the antiviral response, but not earlier, Blimp-1 recruited the histone-modifying enzymes G9a and HDAC2 to the Il2ra and Cd27 loci, thereby repressing expression of these genes. In the absence of Blimp-1, Il2ra and Cd27 exhibited enhanced histone H3 acetylation and reduced histone H3K9 trimethylation. These data elucidate a central mechanism by which Blimp-1 acts as an epigenetic regulator and enhances the numbers of short-lived effector cells while suppressing the development of memory-precursor CD8⁺ T cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / virology
  • Disease Progression
  • Epigenesis, Genetic / immunology*
  • Histone Deacetylase 2 / genetics
  • Histone Deacetylase 2 / immunology
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / immunology
  • Histones / genetics
  • Histones / immunology
  • Humans
  • Immunologic Memory
  • Interleukin-2 Receptor alpha Subunit / antagonists & inhibitors
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymphocytic Choriomeningitis / genetics*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology*
  • Methylation
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Data
  • Positive Regulatory Domain I-Binding Factor 1
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / immunology
  • Signal Transduction
  • Transcription Factors / genetics*
  • Transcription Factors / immunology
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / antagonists & inhibitors
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology

Substances

  • Histones
  • Il2ra protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Prdm1 protein, mouse
  • RNA, Small Interfering
  • Transcription Factors
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • Positive Regulatory Domain I-Binding Factor 1
  • G9a protein, mouse
  • Histone-Lysine N-Methyltransferase
  • Hdac2 protein, mouse
  • Histone Deacetylase 2

Associated data

  • GENBANK/GSE48358