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Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours.

Abstract

Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses. However, the molecular signals that control TRM cell differentiation and homeostasis are not fully understood. Here we show that mouse TRM precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of TRM cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8+ T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of TRM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.

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  • Authors+Show Affiliations

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    Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.

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    Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.

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    Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.

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    Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, California, USA.

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    Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.

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    Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.

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    Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.

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    Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.

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    Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.

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    Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA. Division of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California, USA.

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    Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, California, USA. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA. Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.

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    Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, Florida, USA.

    Division of Biological Sciences, University of California, San Diego, La Jolla, California, USA.

    Source

    Nature 552:7684 2017 12 14 pg 253-257

    MeSH

    Adoptive Transfer
    Animals
    CD8-Positive T-Lymphocytes
    Cell Differentiation
    Cell Proliferation
    Chromatin
    Core Binding Factor Alpha 3 Subunit
    Disease Models, Animal
    Female
    Gene Expression Regulation
    Homeostasis
    Humans
    Immunologic Memory
    Lymphocytes, Tumor-Infiltrating
    Male
    Melanoma
    Mice
    Organ Specificity
    Survival Analysis
    T-Lymphocyte Subsets

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    29211713