Chronic virus infection enforces demethylation of the locus that encodes PD-1 in antigen-specific CD8+ T cells

• Type of Material: Article
• Authors: Benjamin Alan Youngblood, Emory University; Kenneth J. Oestreich, Emory University; Sang-Jun Ha, Emory University; Jaikumar Duraiswamy, Emory University; Rama Akondy, Emory University; Erin E. West, Emory University; Zhengyu Wei, University of Pennsylvania; Peiyuan Lu, Emory University; James W. Austin, Emory University; James L. Riley, Emory University; Jeremy Boss, Emory University; Rafi Ahmed, Emory University
• Language: English
• Date: 2011-09-23
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016%2Fj.immuni.2011.06.015
• Title of Journal or Parent Work: Immunity
• ISSN: 1074-7613
• Volume: 35
• Issue: 3
• Start Page: 400
• End Page: 412
• Grant/Funding Information: This work was supported by the National Institutes of Health (NIH) grant 1 P01 AI080192-01 (to R.A. and J.M.B.), grant 2 R37 AI30048-17 (to R.A.), grant AHMED05GCGH0 (to R.A.), the American Cancer Society (ACS) postdoctoral fellowship PF-09-134-01-MPC (to B.A.Y.), and the Korea Research Foundation (KRF) grant funded by the Korea government (MEST) No. 2010-0004892 (to S.J.H.).
• Research Categories: Biology, Microbiology; Health Sciences, Immunology

Abstract

SUMMARY Functionally exhausted T cells express high levels of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. Using human and murine systems of acute and chronic viral infections we analyzed epigenetic regulation of PD-1 expression during CD8 T cell differentiation. During acute infection, naïve to effector CD8 T cell differentiation was accompanied by a transient loss of DNA methylation of the Pdcd1 locus that was directly coupled to the duration and strength of TCR signaling. Further differentiation into functional memory cells coincided with Pdcd1 remethylation providing an adapted program for regulation of PD-1 expression. In contrast, the Pdcd1 regulatory region was completely demethylated in exhausted CD8 T cells and remained unmethylated even when virus titers decreased. This lack of DNA remethylation leaves the Pdcd1 locus poised for rapid expression, potentially providing a signal for premature termination of antiviral functions.