TY - JOUR
T1 - Chronic Virus Infection Enforces Demethylation of the Locus that Encodes PD-1 in Antigen-Specific CD8+ T Cells
AU - Youngblood, Ben
AU - Oestreich, Kenneth J.
AU - Ha, Sang Jun
AU - Duraiswamy, Jaikumar
AU - Akondy, Rama S.
AU - West, Erin E.
AU - Wei, Zhengyu
AU - Lu, Peiyuan
AU - Austin, James W.
AU - Riley, James L.
AU - Boss, Jeremy M.
AU - Ahmed, Rafi
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2011/9/23
Y1 - 2011/9/23
N2 - Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By 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, naive 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 T cell receptor 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.
AB - Functionally exhausted T cells have high expression of the PD-1 inhibitory receptor, and therapies that block PD-1 signaling show promise for resolving chronic viral infections and cancer. By 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, naive 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 T cell receptor 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.
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U2 - 10.1016/j.immuni.2011.06.015
DO - 10.1016/j.immuni.2011.06.015
M3 - Article
C2 - 21943489
AN - SCOPUS:80053137239
VL - 35
SP - 400
EP - 412
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 3
ER -