Meningeal Type-2 Innate Lymphoid Cells Emerge as Novel Regulators of Microglial Activation and Blood-Brain Barrier Stability: A Central Role for IL-10

Innate lymphoid cell (ILC) cytokine signatures mirror those of T helper subsets, but ILCs differ substantially as far as biological role. Tissue-resident and antigen-independent, ILCs mediate induction and resolution of inflammation, tissue homeostasis, and barrier maintenance. Although extensively character-ized in periphery, ILCs were newly identified as resident in central nervous system (CNS) meninges, and are less well-understood within this novel context. Here we show that ILC-deficient mice exhibit enhanced microglial reactivity, amplified neuroinflammatory responses and blood-brain barrier (BBB) permeability. Accordingly, transcriptomic and functional examination revealed meningeal ILC2s as vigorous interleukin (IL)-10 producers. Mechanistic relevance was demonstrated by amelioration of neuroinflammation following meningeal engraftment of adoptively-transferred wild type — but not IL-10-deficient — ILC2s. Notably, ILC2s from murine bone marrow and human blood also showed IL-10 competency, suggesting a previously-unappreciated immunoregulatory role for canonical ILC2s. Collectively, these findings reveal meningeal ILC2s as suppressors of neuroinflammation — suggesting potential for ILC2-based cell therapies in CNS pathology.