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Cited by 549T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection

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Yao, Chen, Sun, Hong-Wei, Lacey, Neal E., Ji, Yun, Moseman, E. Ashley, Shih, Han-Yu, Heuston, Elisabeth F., Kirby, Martha +14 more·2019·Nature Immunology
DOI 10.1038/s41590-019-0403-4PMC PMC6588409
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Abstract

Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.

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  • Based on comparisons of single-cell transcriptomes, pLN TCF1hi AP in T1D have globally distinct gene-expression patterns compared with TCF1hi progenitor exhausted CD8 T cells in chronic viral infection.

    “However, based on comparisons of single-cell transcriptomes, pLN TCF1hi AP in T1D have globally distinct gene-expression patterns compared with TCF1hi progenitor exhausted CD8 T cells in chronic viral infection24 (Extended Data Fig. 10).”

    From An autoimmune stem-like CD8 T cell population drives type 1 diabetes (2022) · cites this paper as [24]

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Authors
Yao, C., Sun, H.-W., Lacey, N. E., Ji, Y., Moseman, E. A., Shih, H.-Y., Heuston, E. F., Kirby, M., Anderson, S., Cheng, J., Khan, O., Handon, R., Reilley, J., Fioravanti, J., Hu, J., Gossa, S., Wherry, E. J., Gattinoni, L., McGavern, D. B., O’Shea, J. J., Schwartzberg, P. L., & Wu, T.
Affiliations
  • National Institutes of Health (US)
  • University of Pennsylvania (US)
Corresponding author
  • O’Shea, John J.
  • Schwartzberg, Pamela L.
  • Wu, Tuoqi
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2019-06-17
Volume
20
Issue
7
Pages
890-901
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/s41590-019-0403-4
PMC
PMC6588409
OpenAlex
W2951520325
Cited by
549
References
11
Citations by year
2026: 50 · 2025: 74 · 2024: 69 · 2023: 90 · 2022: 69 · 2021: 97 · 2020: 84 · 2019: 16
FWCI
26.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (Z99 AI999999)
  • National Institute on Aging (K99 AG056524, R00AG056524)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
TOX transcription factor, chronic viral infection, memory precursor cells, T cell stemness, T cell reprogramming, histone modifications, epigenetic regulation, T cell differentiation, antiviral immunity, T cell self-renewal
MeSH terms
Animals, Gene Expression Regulation, Immunologic Memory, Infections, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Time Factors, Biomarkers, Homeodomain Proteins, CD8-Positive T-Lymphocytes, Gene Expression Profiling, Epigenesis, Genetic, Chromatin Immunoprecipitation, Mice, Host-Pathogen Interactions, Single-Cell Analysis, High-Throughput Nucleotide Sequencing, Transcriptome

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