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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)¹

Yasuto Araki^*, Monchou Fann^*, Robert Wersto and Nan-ping Weng^2,*

^* Laboratory of Immunology and Flow Cytometry Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Intramural Research Program of the National Institute on Aging and National Cancer Institute, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Nan-ping Weng, 5600 Nathan Shock Drive, Baltimore, MD 21224. E-mail address: wengn{at}mail.nih.gov

³ Abbrevations used in this paper: HAT, histone acetyltransferase; PRF1, perforin 1; GZMB, granzyme B; HDAC, histone deacetylase; ChIP, chromatin immunoprecipitation.