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Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics
Open accessAbstract
Naïve CD8+ T cells can differentiate into effector (T eff), memory (T mem) or exhausted (T ex) T cells. These developmental pathways are associated with distinct transcriptional and epigenetic changes that endow cells with different functional capacities and therefore therapeutic potential. The molecular circuitry underlying these developmental trajectories and the extent of heterogeneity within T eff, T mem and T ex populations remain poorly understood. Here, we used the lymphocytic choriomeningitis virus model of acute-resolving and chronic infection to address these gaps by applying longitudinal single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses. These analyses uncovered new subsets, including a subpopulation of T ex cells expressing natural killer cell-associated genes that is dependent on the transcription factor Zeb2, as well as multiple distinct TCF-1+ stem/progenitor-like subsets in acute and chronic infection. These data also revealed insights into the reshaping of T ex subsets following programmed death 1 (PD-1) pathway blockade and identified a key role for the cell stress regulator, Btg1, in establishing the T ex population. Finally, these results highlighted how the same biological circuits such as cytotoxicity or stem/progenitor pathways can be used by CD8+ T cell subsets with highly divergent underlying chromatin landscapes generated during different infections.
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“Compared to Tpex and tTex cells, cTem cells had transcriptomes more enriched in antigen-specific effector memory T cells in mice infected with the acute Armstrong strain of lymphocytic choriomeningitis virus (LCMV) and less enriched in exhausted T cells from chronic LCMV infection.61”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [61]
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Self-citation
Metadata
- Authors
- Giles, J. R., Ngiow, S. F., Manne, S., Baxter, A. E., Khan, O., Wang, P., Staupe, R., Abdel-Hakeem, M. S., Huang, H., Mathew, D., Painter, M. M., Wu, J. E., Huang, Y. J., Goel, R. R., Yan, P. K., Karakousis, G. C., Xu, X., Mitchell, T. C., Huang, A. C., & Wherry, E. J.
- Affiliations
- University of Pennsylvania (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Emory University (US)
- Parker Institute for Cancer Immunotherapy (US)
- Corresponding author
- Wherry, E. John
- ORCID
- Giles, Josephine R.
- Ngiow, Shin Foong
- Manne, Sasikanth
- Baxter, Amy E.
- Khan, Omar
- Wang, Ping
- Staupe, Ryan
- Abdel-Hakeem, Mohamed S.
- Huang, Hua
- Mathew, Divij
- Painter, Mark M.
- Wu, Jennifer E.
- Huang, Yinghui Jane
- Goel, Rishi R.
- Yan, Patrick K.
- Karakousis, Giorgos C.
- Xu, Xiaowei
- Mitchell, Tara C.
- Huang, Alexander C.
- Wherry, E. John
- Venue
- Nature Immunology
- Published
- 2022-10-21
- Volume
- 23
- Issue
- 11
- Pages
- 1600-1613
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC10408358
- OpenAlex
- W4307040885
- Cited by
- 264
- References
- 55
- Citations by year
- 2026: 71 · 2025: 81 · 2024: 65 · 2023: 44 · 2022: 3
- FWCI
- 18.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Science Foundation (P50 CA174523)
- Cancer Research Institute
- Damon Runyon Cancer Research Foundation
- American Association of Immunologists
- Parker Institute for Cancer Immunotherapy
- National Institutes of Health (CA210944, AI082630, AI149680, CA009140, AI108545)
- Stand Up To Cancer
- National Health and Medical Research Council (1111469)
- National Cancer Institute (K08CA230157, T32CA009140, P50CA174523, P50CA261608, P01CA210944)
- National Institute of Allergy and Infectious Diseases (AI 082630, AI108545, F30AI129263, U19AI149680, AI149680, U19AI117950, R01AI155577, U19AI082630, P01AI108545)
- National Institute of Diabetes and Digestive and Kidney Diseases (U01DK127768)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- CD8+ T cells, T cell exhaustion, effector T cells, memory T cells, T cell differentiation, lymphocytic choriomeningitis virus, chronic infection, acute infection, ZEB2, anti-PD-1 therapy, BTG1, chromatin accessibility, transcriptional circuits, cytotoxicity, single-cell transcriptomics, single-cell epigenomics
- MeSH terms
- Chromatin, Humans, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, CD8-Positive T-Lymphocytes, Epigenesis, Genetic, Transcriptome
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