title: Epigenetic modifications induced by Blimp-1 Regulate CD8⁺ T cell memory progression during acute virus infection.
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.
authors.affiliation: Dept. of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Hyun Mu
authors.initials: HM
authors.lastname: Shin
authors.affiliation: Dept. of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Kapoor
authors.affiliation: Dept. of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA and Howard Hughes Medical Institute.
authors.forename: Tianxia
authors.initials: T
authors.lastname: Guan
authors.affiliation: Dept. of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA and Howard Hughes Medical Institute.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Kaech
authors.affiliation: Dept. of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.affiliation: Dept. of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Berg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D018450:Disease Progression; D044127:Epigenesis, Genetic / Q000276:immunology*; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000276:immunology; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000276:immunology; D006657:Histones / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D000074462:Positive Regulatory Domain I-Binding Factor 1; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics* / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology
chemical_list: D006657:Histones; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C513258:Prdm1 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D000074462:Positive Regulatory Domain I-Binding Factor 1; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2