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Nat Immunol. 2019 Jul;20(7):890-901. doi: 10.1038/s41590-019-0403-4. Epub 2019 Jun 17.

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

Author information

1
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
2
National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
3
Cellular Biomedicine Group, Gaithersburg, MD, USA.
4
National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
5
Department of Immunology, Duke University School of Medicine, Durham, NC, USA.
6
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
7
Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School Medicine, Philadelphia, PA, USA.
8
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
9
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. osheaj@arb.niams.nih.gov.
10
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. pams@nih.gov.
11
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. pams@nih.gov.
12
National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. tuoqi.wu@ucdenver.edu.
13
National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. tuoqi.wu@ucdenver.edu.
14
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA. tuoqi.wu@ucdenver.edu.

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.

PMID:
31209400
PMCID:
PMC6588409
[Available on 2019-12-17]
DOI:
10.1038/s41590-019-0403-4
[Indexed for MEDLINE]

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