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


Liliana M Sanmarco, Michael A Wheeler, Cristina Gutiérrez-Vázquez, Carolina Manganeli Polonio, Mathias Linnerbauer, Felipe A Pinho-Ribeiro, Zhaorong Li, Federico Giovannoni, Katelyn V Batterman, Giulia Scalisi, Stephanie EJ Zandee, Evelyn S Heck, Moneera Alsuwailm, Douglas L Rosene, Burkhard Becher, Isaac M Chiu, Alexandre Prat, and Francisco J Quintana. 2021. “Gut-licensed IFNγ+ NK cells drive LAMP1+ TRAIL+ anti-inflammatory astrocytes.” Nature, 590, 7846, Pp. 473-479. Copy at
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Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions. 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 LAMP1 and the death receptor ligand TRAIL. LAMP1TRAIL 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 LAMP1TRAIL 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.
Last updated on 04/12/2021