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.

星形胶质细胞是中枢神经系统 (CNS) 中丰富的神经胶质细胞，具有重要的稳态和促进疾病的功能¹ 。然而，人们对星形胶质细胞的稳态抗炎活性及其调节知之甚少。在这里，我们利用高通量流式细胞术筛选、单细胞 RNA 测序和基于 CRISPR-Cas9 的小鼠体内细胞特异性遗传扰动，鉴定了表达溶酶体蛋白 LAMP1 ²和死亡受体配体 TRAIL 的星形胶质细胞亚群³ . LAMP1 ⁺ TRAIL ⁺星形胶质细胞通过 TRAIL-DR5 信号传导诱导 T 细胞凋亡，从而限制 CNS 炎症。在稳态条件下，星形胶质细胞中 TRAIL 的表达由脑膜自然杀伤 (NK) 细胞产生的干扰素-γ (IFNγ) 驱动，其中 IFNγ 表达受肠道微生物组调节。星形胶质细胞中的 TRAIL 表达受到炎症环境下 T 细胞和小胶质细胞产生的分子的抑制。总而言之，我们表明 LAMP1 ⁺ TRAIL ⁺星形胶质细胞通过诱导 T 细胞凋亡来限制 CNS 炎症，并且该星形胶质细胞亚群由微生物组许可的脑膜 IFNγ ⁺ NK 细胞维持。