Demethylation of the PD-1 Promoter Is Imprinted during the Effector Phase of CD8 T Cell Exhaustion

• Type of Material: Article
• Authors: Eunseon Ahn, Emory University; Benjamin Youngblood, Emory University; Junghwa Lee, Emory University; Judong Lee, Emory University; Surojit Sarkar, University of Washington; Rafi Ahmed, Emory University
• Language: English
• Date: 2016-10-01
• Publisher: American Society for Microbiology
• Publication Version: Final Published Version
• Copyright Statement: © 2016, American Society for Microbiology. All Rights Reserved.
• Final Published Version (URL): http://dx.doi.org/10.1128/JVI.00798-16
• Title of Journal or Parent Work: Journal of Virology
• ISSN: 0022-538X
• Volume: 90
• Issue: 19
• Start Page: 8934
• End Page: 8946
• Grant/Funding Information: National Institutes of Health (NIH) (RO1 AI30048 and PO1 AI056299).; This work, including the efforts of Eunseon Ahn, was funded by National Research Foundation (NRF) (E00024).; E. Ahn received a postdoctoral fellowship (E00024) through the Basic Science Research Program of the National Research Foundation of Korea (NRF), funded by the Ministry of Education.; This work, including the efforts of Rafi Ahmed, was funded by NHS
• Keywords: IMMUNOSUPPRESSION; INHIBITORY RECEPTOR PD-1; Science & Technology; EXPRESSION; Life Sciences & Biomedicine; ANTI-PD-L1 ANTIBODY; Virology; CANCER; PERSISTENCE; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; RESPONSES; CHRONIC VIRAL-INFECTION; DENDRITIC CELLS
• Research Categories: Biology, Virology; Health Sciences, Immunology; Health Sciences, Oncology

Abstract

PD-1 is an inhibitory receptor that has a major role in T cell dysfunction during chronic infections and cancer. While demethylation of the PD-1 promoter DNA is observed in exhausted T cells isolated from chronically infected individuals, little is known about when this stable demethylation of PD-1 promoter DNA is programmed during the course of a chronic infection. To assess if PD-1 promoter DNA demethylation is impacted by prolonged stimulation during effector phase of chronic infection, we adoptively transferred virus-specific day 8 effector CD8 T cells from mice infected with lymphocytic choriomeningitis virus (LCMV) clone 13 into recipient mice that had cleared an acute infection. We observed that LCMV-specific CD8 T cells from chronically infected mice maintained their surface expression of PD-1 even after transfer into acute immune mice until day 45 posttransfer. Interestingly, the PD-1 transcriptional regulatory region continued to remain unmethylated in these donor CD8 T cells generated from a chronic infection. The observed maintenance of PD-1 surface expression and the demethylated PD-1 promoter were not a result of residual antigen in the recipient mice, because similar results were seen when chronic infection-induced effector cells were transferred into mice infected with a variant strain of LCMV (LCMV V35A) bearing a mutation in the cognate major histocompatibility complex class I (MHC-I) epitope that is recognized by the donor CD8 T cells. Importantly, the maintenance of PD-1 promoter demethylation in memory CD8 T cells was coupled with impaired clonal expansion and higher PD-1 re-expression upon secondary challenge. These data show that the imprinting of the epigenetic program of the inhibitory receptor PD-1 occurs during the effector phase of chronic viral infection.