Group 2 innate lymphoid cells activate myelin-reactive T cells to augment neuroinflammation.

The meninges are a gateway for pathogenic T cells to enter the central nervous system (CNS). They possess a diverse repertoire of immune cells that orchestrate CNS inflammation and autoimmunity, yet the underlying mechanisms are poorly understood. Here, we report that group 2 innate lymphoid cells (ILC2s) accumulated in the dura as experimental autoimmune encephalomyelitis (EAE) progressed. Single-cell RNA sequencing and flow cytometry analyses revealed distinct features of ILC2s, including expression of MHC class II. ILC2s acted as antigen-presenting cells to activate and expand myelin-reactive T cells in an MHC class II-dependent manner. ILC2-mediated expansion of myelin-reactive T cells increased expression of cytokines IFN-γ and IL-17A. Genetic ablation of ILC2s or of H2-Ab1 in ILC2s alleviated neuroinflammation and CNS demyelination during EAE. These findings revealed a role of ILC2s in neuroinflammation via instructing myelin-reactive T cells, implying targeting ILC2s may be an avenue to restrict CNS inflammation and autoimmunity.