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.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Animals
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology
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CD8-Positive T-Lymphocytes / virology
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Disease Progression
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Epigenesis, Genetic / immunology*
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Histone Deacetylase 2 / genetics
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Histone Deacetylase 2 / immunology
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / immunology
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Histones / genetics
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Histones / immunology
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Humans
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Immunologic Memory
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Interleukin-2 Receptor alpha Subunit / antagonists & inhibitors
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Interleukin-2 Receptor alpha Subunit / genetics
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Interleukin-2 Receptor alpha Subunit / immunology
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Lymphocytic Choriomeningitis / genetics*
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Lymphocytic Choriomeningitis / immunology
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Lymphocytic Choriomeningitis / pathology
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Lymphocytic Choriomeningitis / virology
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Lymphocytic choriomeningitis virus / immunology*
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Methylation
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Mice
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Mice, Transgenic
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Molecular Sequence Data
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Positive Regulatory Domain I-Binding Factor 1
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RNA, Small Interfering / genetics
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RNA, Small Interfering / immunology
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Signal Transduction
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Transcription Factors / genetics*
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Transcription Factors / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / antagonists & inhibitors
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
Substances
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Histones
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Il2ra protein, mouse
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Interleukin-2 Receptor alpha Subunit
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Prdm1 protein, mouse
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RNA, Small Interfering
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Transcription Factors
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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Positive Regulatory Domain I-Binding Factor 1
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G9a protein, mouse
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Histone-Lysine N-Methyltransferase
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Hdac2 protein, mouse
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Histone Deacetylase 2