Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B).
To understand the mechanism regulating the effector function of memory CD8 T cells, we examined expression and chromatin state of a key transcription factor (eomesodermin, EOMES) and two of its targets: perforin (PRF1) and granzyme B (GZMB). Accessible chromatin associated histone 3 lysine 9 acetylation (H3K9Ac) was found significantly higher at the proximal promoter and the first exon region of all three genes in memory CD8 T cells than in naive CD8 T cells. Correspondingly, EOMES and PRF1 were constitutively higher expressed in memory CD8 T cells than in naive CD8 T cells at resting and activated states. In contrast, higher expression of GZMB was induced in memory CD8 T cells than in naive CD8 T cells only after activation. Regardless of their constitutive or inducible expression, decreased H3K9Ac levels after treatment with a histone acetyltransferase inhibitor (Curcumin) led to decreased expression of all three genes in activated memory CD8 T cells. These findings suggest that H3K9Ac associated accessible chromatin state serves as a corner stone for the differentially high expression of these effector genes in memory CD8 T cells. Thus, epigenetic changes mediated via histone acetylation may provide a chromatin "memory" for the rapid and robust transcriptional response of memory CD8 T cells.
Araki
Yasuto
Y
Laboratory of Immunology and Flow Cytometry Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
Fann
Monchou
M
Wersto
Robert
R
Weng
Nan-Ping
NP
D000107:Acetylation; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D002469:Cell Separation; D002843:Chromatin / Q000378:metabolism; D053804:Granzymes / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007156:Immunologic Memory / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008239:Lysine / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000235:genetics / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*; D000099186:Histone Deacetylase 3
D002843:Chromatin; D053804:Granzymes; D006655:Histone Deacetylases; D006657:Histones; D008239:Lysine; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D020825:T-Box Domain Proteins; D000099186:Histone Deacetylase 3; C491199:EOMES protein, human; C510468:PRF1 protein, human; C509213:GZMB protein, human