Gut-licensed IFN gamma(+) NK cells drive LAMP1(+)TRAIL(+) anti-inflammatory astrocytes

Author(s):Show less -

Sanmarco, Liliana M. ^[1] ; Wheeler, Michael A. ^{[2, 1]} ; Gutierrez-Vazquez, Cristina ^[1] ; Polonio, Carolina Manganeli ^[1] ; Linnerbauer, Mathias ^[1] ; Pinho-Ribeiro, Felipe A. ^[3] ; Li, Zhaorong ^{[2, 1]} ; Giovannoni, Federico ^[1] ; Batterman, Katelyn V. ^[4] ; Scalisi, Giulia ^[1] ; Zandee, Stephanie E. J. ^{[5, 6]} ; Heck, Evelyn S. ^[1] ; Alsuwailm, Moneera ^{[1, 7]} ; Rosene, Douglas L. ^[4] ; Becher, Burkhard ^[8] ; Chiu, Isaac M. ^[3] ; Prat, Alexandre ^{[5, 6]} ; Quintana, Francisco J. ^{[2, 1]}

Affiliation

^[1] Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Boston, MA 02115 - USA

^[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 - USA

^[3] Harvard Med Sch, Dept Immunol, Boston, MA 02115 - USA

^[4] Boston Univ, Sch Med, Dept Anat & Neurobiol, Boston, MA 02118 - USA

^[5] CHUM, Ctr Rech, Neuroimmunol Unit, Montreal, PQ - Canada

^[6] Univ Montreal, Fac Med, Dept Neurosci, Montreal, PQ - Canada

^[7] King Abdulaziz City Sci & Technol KACST, Ctr Excellence Biomed, Joint Ctr Excellence Program, Riyadh - Saudi Arabia

^[8] Univ Zurich, Inst Expt Immunol, Zurich - Switzerland

• Document type: Journal article
• Source: Nature; v. 590, n. 7846, p. 473+, FEB 18 2021.
• Web of Science Citations: 32

Abstract

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. (AU)

• FAPESP's process: 19/13731-0 - MicroRNAs, neurodevelopment and antiviral immune response: how they can be connected?
• Grantee: Carolina Manganeli Polonio
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate