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Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes

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Listed:
  • Liliana M. Sanmarco

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Michael A. Wheeler

    (Brigham and Women’s Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Cristina Gutiérrez-Vázquez

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Carolina Manganeli Polonio

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Mathias Linnerbauer

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Felipe A. Pinho-Ribeiro

    (Harvard Medical School)

  • Zhaorong Li

    (Brigham and Women’s Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

  • Federico Giovannoni

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Katelyn V. Batterman

    (Boston University School of Medicine)

  • Giulia Scalisi

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Stephanie E. J. Zandee

    (Centre de Recherche du CHUM
    Faculty of Medicine, Université de Montréal)

  • Evelyn S. Heck

    (Brigham and Women’s Hospital, Harvard Medical School)

  • Moneera Alsuwailm

    (Brigham and Women’s Hospital, Harvard Medical School
    King Abdulaziz City for Science and Technology (KACST))

  • Douglas L. Rosene

    (Boston University School of Medicine)

  • Burkhard Becher

    (University of Zurich)

  • Isaac M. Chiu

    (Harvard Medical School)

  • Alexandre Prat

    (Centre de Recherche du CHUM
    Faculty of Medicine, Université de Montréal)

  • Francisco J. Quintana

    (Brigham and Women’s Hospital, Harvard Medical School
    Broad Institute of MIT and Harvard)

Abstract

Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions1. However, little is known about the homeostatic anti-inflammatory activities of astrocytes and their regulation. Here, using high-throughput flow cytometry screening, single-cell RNA sequencing and CRISPR–Cas9-based cell-specific in vivo genetic perturbations in mice, we identify a subset of astrocytes that expresses the lysosomal protein LAMP12 and the death receptor ligand TRAIL3. LAMP1+TRAIL+ astrocytes limit inflammation in the CNS by inducing T cell apoptosis through TRAIL–DR5 signalling. In homeostatic conditions, the expression of TRAIL in astrocytes is driven by interferon-γ (IFNγ) produced by meningeal natural killer (NK) cells, in which IFNγ expression is modulated by the gut microbiome. TRAIL expression in astrocytes is repressed by molecules produced by T cells and microglia in the context of inflammation. Altogether, we show that LAMP1+TRAIL+ astrocytes limit CNS inflammation by inducing T cell apoptosis, and that this astrocyte subset is maintained by meningeal IFNγ+ NK cells that are licensed by the microbiome.

Suggested Citation

  • Liliana M. Sanmarco & Michael A. Wheeler & Cristina Gutiérrez-Vázquez & Carolina Manganeli Polonio & Mathias Linnerbauer & Felipe A. Pinho-Ribeiro & Zhaorong Li & Federico Giovannoni & Katelyn V. Batt, 2021. "Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes," Nature, Nature, vol. 590(7846), pages 473-479, February.
    • Handle: RePEc:nat:nature:v:590:y:2021:i:7846:d:10.1038_s41586-020-03116-4
    DOI: 10.1038/s41586-020-03116-4
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