title: Epigenetic repression of interleukin 2 expression in senescent CD4+ T cells during chronic HIV type 1 infection.
abstract: The molecular mechanisms for IL2 gene-specific dysregulation during chronic human immunodeficiency virus type 1 (HIV-1) infection are unknown. Here, we investigated the role of DNA methylation in suppressing interleukin 2 (IL-2) expression in memory CD4(+) T cells during chronic HIV-1 infection. We observed that CpG sites in the IL2 promoter of CD4(+) T cells were fully methylated in naive CD4(+) T cells and significantly demethylated in the memory populations. Interestingly, we found that the memory cells that had a terminally differentiated phenotype and expressed CD57 had increased IL2 promoter methylation relative to less differentiated memory cells in healthy individuals. Importantly, early effector memory subsets from HIV-1-infected subjects expressed high levels of CD57 and were highly methylated at the IL2 locus. Furthermore, the increased CD57 expression on memory CD4(+) T cells was inversely correlated with IL-2 production. These data suggest that DNA methylation at the IL2 locus in CD4(+) T cells is coupled to immunosenescence and plays a critical role in the broad dysfunction that occurs in polyclonal T cells during HIV-1 infection.
authors.affiliation: Division of Infectious Diseases, Advanced Clinical Research Center International Research Center for Infectious Diseases.
authors.forename: Kaori
authors.initials: K
authors.lastname: Nakayama-Hosoya
authors.affiliation: Research Center for Asian Infectious Diseases.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Ishida
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Ben
authors.initials: B
authors.lastname: Youngblood
authors.affiliation: Division of Infectious Diseases, Advanced Clinical Research Center International Research Center for Infectious Diseases.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Division of Infectious Diseases, Advanced Clinical Research Center International Research Center for Infectious Diseases.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Hosoya
authors.affiliation: Division of Infectious Diseases, Advanced Clinical Research Center.
authors.forename: Michiko
authors.initials: M
authors.lastname: Koga
authors.affiliation: Department of Infectious Diseases and Applied Immunology, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Koibuchi
authors.affiliation: Division of Infectious Diseases, Advanced Clinical Research Center International Research Center for Infectious Diseases Research Center for Asian Infectious Diseases Department of Infectious Diseases and Applied Immunology, IMSUT Hospital, Institute of Medical Science, University of Tokyo, Japan.
authors.forename: Aikichi
authors.initials: A
authors.lastname: Iwamoto
authors.affiliation: Division of Infectious Diseases, Advanced Clinical Research Center.
authors.forename: Ai
authors.initials: A
authors.lastname: Kawana-Tachikawa
mesh_terms: D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018959:CD57 Antigens / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D063185:Epigenetic Repression; D015658:HIV Infections / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008875:Middle Aged; D011401:Promoter Regions, Genetic
chemical_list: D018959:CD57 Antigens; C508594:IL2 protein, human; D007376:Interleukin-2
keywords: CD4+ T-cell dysfunction; DNA methylation; HIV-1; T-cell differentiation; immunosenescence; repression of IL-2 expression