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

Authors: Sanmarco, Liliana M.; Wheeler, Michael A.; Gutiérrez-Vázquez, Cristina; Polonio, Carolina Manganeli; Linnerbauer, Mathias; Pinho-Ribeiro, Felipe A.; Li, Zhaorong; Giovannoni, Federico; Batterman, Katelyn V.; Scalisi, Giulia; Zandee, Stephanie E. J.; Heck, Evelyn S.; Alsuwailm, Moneera; Rosene, Douglas L.; Becher, Burkhard; Chiu, Isaac M.; Prat, Alexandre; Quintana, Francisco J.

Online: https://www.nature.com/articles/s41586-020-03116-4

Issue: Nature. 2021 Feb;590(7846):473-479.


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.