Changes in histone acetylation and methylation that are important for persistent but not transient expression of CCR4 in human CD4+ T cells.
Although regulation of CXCR3 and CCR4 is related to Th1 and Th2 differentiation, respectively, many CXCR3(+) and CCR4(+) cells do not express IFN-γ and/or IL-4, suggesting that the chemokine receptor genes might be inducible by mechanisms that are lineage-independent. We investigated the regulation of CXCR3 versus IFNG, and CCR4 versus IL4 in human CD4(+) T cells by analyzing modifications of histone H3. In naïve cord-blood cells, under nonpolarizing conditions not inducing IL4, CCR4 was induced to high levels without many of the activation-associated changes in promoter histone H3 found for both IL4 and CCR4 in Th2 cells. Importantly, CCR4 expression was stable in Th2 cells, but fell in nonpolarized cells after the cells were rested; this decline could be reversed by increasing histone acetylation using sodium butyrate. Patterns of histone H3 modifications in CXCR3(+) CCR4(-) and CXCR3(-) CCR4(+) CD4(+) T-cell subsets from adult blood matched those in cells cultured under polarizing conditions in vitro. Our data show that high-level lineage-independent induction of CCR4 can occur following T-cell activation without accessibility-associated changes in histone H3, but that without such changes expression is transient rather than persistent.
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda M, USA.
Satya P
SP
Singh
Laboratory of Molecular Immunoregulation, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, BRAZIL.
Maristela M
MM
de Camargo
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda M, USA.
Hongwei H
HH
Zhang
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda M, USA.
John F
JF
Foley
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda M, USA.
Michael N
MN
Hedrick
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda M, USA.
Joshua M
JM
Farber
D000107:Acetylation / Q000187:drug effects; D002087:Butyrates / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006657:Histones / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008745:Methylation / Q000187:drug effects; D054398:Receptors, CCR4 / Q000096:biosynthesis / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000096:biosynthesis / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D002087:Butyrates; C515354:CCR4 protein, human; C515187:CXCR3 protein, human; D006657:Histones; C508598:IL4 protein, human; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D015847:Interleukin-4