Epigenetic signature of PD-1+TCF1+CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade

• Type of Material: Article
• Authors: Rohit R. Jadhav, Stanford University; Sejin Im, Emory University; Bin Hu, Stanford University; Masao Hashimoto, Emory University; Peng Li, National Institutes of Health, Bethesda; Jian-Xin Lin, National Institutes of Health, Bethesda; Warren J. Leonard, National Institutes of Health, Bethesda; William J. Greenleaf, Stanford University; Rafi Ahmed, Emory University; Jorg J. Goronzy, Stanford University
• Language: English
• Date: 2019-07-09
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2019 National Academy of Sciences. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1903520116
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 116
• Issue: 28
• Start Page: 14113
• End Page: 14118
• Grant/Funding Information: P.L., J.-X.L., and W.J.L. are supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute, NIH.; This work was supported by National Institutes of Health U19 AI057266 (to J.J.G.) and R01 AI030048 (to R.A.).
• Keywords: CD8 T cell exhaustion; ATAC-seq; IMPAIRMENT; EFFECTOR; SUBSETS; epigenetic profiles; Multidisciplinary Sciences; MEMORY; EXHAUSTION; Science & Technology; Science & Technology - Other Topics; EXPRESSION; CANCER
• Research Categories: Biology, Genetics; Health Sciences, Immunology

Abstract

We have recently defined a novel population of PD-1 (programmed cell death 1)+ TCF1 (T cell factor 1)+ virus-specific CD8 T cells that function as resource cells during chronic LCMV infection and provide the proliferative burst seen after PD-1 blockade. Such CD8 T cells have been found in other chronic infections and also in cancer in mice and humans. These CD8 T cells exhibit stem-like properties undergoing self-renewal and also differentiating into the terminally exhausted CD8 T cells. Here we compared the epigenetic signature of stem-like CD8 T cells with exhausted CD8 T cells. ATAC-seq analysis showed that stem-like CD8 T cells had a unique signature implicating activity of HMG (TCF) and RHD (NF-κB) transcription factor family members in contrast to higher accessibility to ETS and RUNX motifs in exhausted CD8 T cells. In addition, regulatory regions of the transcription factors Tcf7 and Id3 were more accessible in stem-like cells whereas Prdm1 and Id2 were more accessible in exhausted CD8 T cells. We also compared the epigenetic signatures of the 2 CD8 T cell subsets from chronically infected mice with effector and memory CD8 T cells generated after an acute LCMV infection. Both CD8 T cell subsets generated during chronic infection were strikingly different from CD8 T cell subsets from acute infection. Interestingly, the stem-like CD8 T cell subset from chronic infection, despite sharing key functional properties with memory CD8 T cells, had a very distinct epigenetic program. These results show that the chronic stem-like CD8 T cell program represents a specific adaptation of the T cell response to persistent antigenic stimulation.