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

Nature. 2021 Feb;590(7846):473-479. doi: 10.1038/s41586-020-03116-4. Epub 2021 Jan 6.

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.

Publication types

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

MeSH terms

  • Animals
  • Apoptosis
  • Astrocytes / immunology*
  • Astrocytes / metabolism
  • Biomarkers
  • Central Nervous System / immunology
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control
  • Female
  • Gastrointestinal Microbiome / immunology*
  • Homeostasis
  • Humans
  • Inflammation / immunology
  • Inflammation / prevention & control*
  • Interferon-gamma / immunology*
  • Killer Cells, Natural / immunology*
  • Lysosomal Membrane Proteins / metabolism*
  • Meninges / cytology
  • Meninges / immunology
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*

Substances

  • Biomarkers
  • Lamp1 protein, mouse
  • Lysosomal Membrane Proteins
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Tnfsf10 protein, mouse
  • Interferon-gamma