Gut-Licensed Ifn Gamma(+) Nk Cells Drive Lamp1(+)Trail(+) Anti-Inflammatory Astrocytes

Astrocytes are glial cells that are abundant in the central nervous system (CNS) and that have important homeostatic and disease-promoting functions(1). 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(2) and the death receptor ligand TRAIL(3). 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-gamma (IFN gamma) produced by meningeal natural killer (NK) cells, in which IFN gamma 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 IFN gamma(+) NK cells that are licensed by the microbiome.