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 E. J. Zandee, Evelyn S. Heck, Moneera Alsuwailm, Douglas L. Rosene, Burkhard Becher, Isaac M. Chiu, Alexandre Prat and Francisco J. Quintana ()
Additional contact information
Liliana M. Sanmarco: Brigham and Women’s Hospital, Harvard Medical School
Michael A. Wheeler: Brigham and Women’s Hospital, Harvard Medical School
Cristina Gutiérrez-Vázquez: Brigham and Women’s Hospital, Harvard Medical School
Carolina Manganeli Polonio: Brigham and Women’s Hospital, Harvard Medical School
Mathias Linnerbauer: Brigham and Women’s Hospital, Harvard Medical School
Felipe A. Pinho-Ribeiro: Harvard Medical School
Zhaorong Li: Brigham and Women’s Hospital, Harvard Medical School
Federico Giovannoni: Brigham and Women’s Hospital, Harvard Medical School
Katelyn V. Batterman: Boston University School of Medicine
Giulia Scalisi: Brigham and Women’s Hospital, Harvard Medical School
Stephanie E. J. Zandee: Centre de Recherche du CHUM
Evelyn S. Heck: Brigham and Women’s Hospital, Harvard Medical School
Moneera Alsuwailm: Brigham and Women’s Hospital, Harvard Medical School
Douglas L. Rosene: Boston University School of Medicine
Burkhard Becher: University of Zurich
Isaac M. Chiu: Harvard Medical School
Alexandre Prat: Centre de Recherche du CHUM
Francisco J. Quintana: Brigham and Women’s Hospital, Harvard Medical School

Nature, 2021, vol. 590, issue 7846, 473-479

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-020-03116-4

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