Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation

• Type of Material: Article
• Authors: Mohamed Abdel Hakeem, Emory University; Sasikanth Manne, University of Pennsylvania; Jean-Christophe Beltra, University of Pennsylvania; Erietta Stelekati, University of Pennsylvania; Zeyu Chen, University of Pennsylvania; Kito Nzingha, University of Pennsylvania; Mohammed-Alkhatim Ali, University of Pennsylvania; John L. Johnson, University of Pennsylvania; Josephine R. Giles, University of Pennsylvania; Divij Mathew, University of Pennsylvania; Allison R. Greenplate, University of Pennsylvania; Golnaz Vahedi, University of Pennsylvania; E. John Wherry, University of Pennsylvania
• Language: English
• Date: 2021-08-01
• Publisher: Nature
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41590-021-00975-5
• Title of Journal or Parent Work: Nature Immunology
• Volume: 22
• Issue: 8
• Start Page: 1008
• End Page: 1019
• Grant/Funding Information: This work was supported by NIH grants AI155577, AI105343, AI115712, AI117950, AI108545, AI082630 and CA210944 (to E.J. Wherry). E.J. Wherry is supported by the Parker Institute for Cancer Immunotherapy which supports the cancer immunology program at UPenn. M.S. Abdel-Hakeem is a Cancer Research Institute (CRI) Irvington Postdoctoral Fellow, and is supported by Fonds de Recherche Québec—Santé (FRQS), and Canadian Network on Hepatitis C (CanHepC) Postdoctoral Fellowships. CanHepC is funded by a joint initiative from CIHR (NHC-142832) and the Public Health Agency of Canada.
• Keywords: CD8-Positive T-Lymphocytes; Antigens, Viral; Mice, Inbred C57BL; Epigenesis, Genetic; Mice, Transgenic; Hepatocyte Nuclear Factor 1-alpha; Vero Cells; Animals; Female; Mice; Cricetinae; Transcription, Genetic; Cell Line; Lymphocytic Choriomeningitis; Chlorocebus aethiops; Immunologic Memory; Cell Differentiation; Lymphocytic choriomeningitis virus
• Research Categories: Health Sciences, Immunology; Biology, Cell; Biology, Virology

Abstract

Exhausted CD8 T cells (TEX) are a distinct state of T cell differentiation associated with failure to clear chronic viruses and cancer. Immunotherapies such as PD-1 blockade can reinvigorate TEX cells, but reinvigoration is not durable. A major unanswered question is whether TEX cells differentiate into functional durable memory T cells (TMEM) upon antigen clearance. Here, using a mouse model, we found that upon eliminating chronic antigenic stimulation, TEX cells partially (re)acquire phenotypic and transcriptional features of TMEM cells. These ‘recovering’ TEX cells originated from the T cell factor (TCF-1+) TEX progenitor subset. Nevertheless, the recall capacity of these recovering TEX cells remained compromised as compared to TMEM cells. Chromatin-accessibility profiling revealed a failure to recover core memory epigenetic circuits and maintenance of a largely exhausted open chromatin landscape. Thus, despite some phenotypic and transcriptional recovery upon antigen clearance, exhaustion leaves durable epigenetic scars constraining future immune responses. These results support epigenetic remodeling interventions for TEX cell–targeted immunotherapies.