Antigen presenting group 3 innate lymphoid cells orchestrate neuroinflammation

Abstract

Abstract Pro-inflammatory T cells in the central nervous system (CNS) are causally associated with multiple demyelinating and neurodegenerative diseases, but the pathways controlling these responses remain unclear. Here we define a unique population of group 3 innate lymphoid cells (ILC3s) that infiltrate the CNS in a mouse model of multiple sclerosis. These ILC3s are derived from the circulation, localize in proximity to infiltrating T cells in the CNS, function as antigen presenting cells that restimulate myelin-specific T cells, and are elevated in the blood of individuals with multiple sclerosis. Critically, antigen presentation by ILC3s is required to promote pro-inflammatory T cell responses in the CNS and the development of multiple sclerosis-like disease in mouse models. In contrast, conventional and tissue-resident ILC3s in the periphery do not appear to contribute to disease induction, but rather remain tolerogenic with the potential to limit autoimmune T cells and prevent multiple sclerosis-like disease when experimentally targeted to present myelin antigen. Collectively, our data define an inflammatory ILC3 population that is essential for directly promoting T cell-dependent neuroinflammation in the CNS and reveal the potential to harness peripheral tissue-resident ILC3s for the prevention of autoimmune disease.