Epigenetic mechanisms of age-dependent KIR2DL4 expression in T cells.
Killer Ig-like receptor (KIR) expression is mostly restricted to NK cells controlling their activation. With increasing age, KIRs are expressed on T cells and contribute to age-related diseases. We examined epigenetic mechanisms that determine the competency of T cells to transcribe KIR2DL4. Compared with Jurkat cells and CD4(+)CD28(+) T cells from young individuals, DNA methyltransferase (DNMT) inhibition was strikingly more effective in T cells from elderly adults and the CD4(+)CD28(-) T cell line HUT78 to induce KIR2DL4 transcription. In these susceptible cells, the KIR2DL4 promoter was partially demethylated, and dimethylated H3-Lys 4 was increased, and all other histone modifications were characteristic for an inactive promoter. In comparison, NK cells had a fully demethylated KIR2DL4 promoter and the full spectrum of histone modifications indicative of active transcription with H3 and H4 acetylation, di- and trimethylated H3-Lys 4, and reduced, dimethylated H3-Lys 9. These results suggest that an increased competency of T cells to express KIR2DL4 with aging is conferred by a selective increase in H3-Lys 4 dimethylation and limited DNA demethylation. The partially accessible promoter is sensitive to DNMT inhibition, which is sufficient to induce full transcription without further histone acetylation and methylation.
Li
Guangjin
G
Kathleen B. and Mason I. Lowance Center for Human Immunology and Rheumatology, Emory University School of Medicine, 101 Woodruff Circle, #1003, Atlanta, GA 30322, USA.
Weyand
Cornelia M
CM
Goronzy
Jörg J
JJ
D000107:Acetylation; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D018106:CD28 Antigens / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008239:Lysine / Q000378:metabolism; D009707:Nucleosomes / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054345:Receptors, KIR2DL4 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection
D018106:CD28 Antigens; D015704:CD4 Antigens; D002843:Chromatin; D006657:Histones; C515079:KIR2DL4 protein, human; D009707:Nucleosomes; D012333:RNA, Messenger; D054345:Receptors, KIR2DL4; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D008239:Lysine