Meningeal gd T cells regulate anxiety like behaviors via Il17a signaling on Neurons (PFC neurons)

Interleukin 17a (IL-17a) is a cytokine that has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Recent studies in mouse models of maternal immune activation suggest that IL-17a is also linked to behavioral changes reminiscent of those seen under pathological conditions such as autism spectrum disorders (ASD)1 and in aggregation behavior in Caenorhabditis elegans2, raising the intriguing possibility that this cytokine might have evolved for the homeostatic regulation of neuronal activity. Here, by in-depth cellular and molecular characterization of a unique population of meningeal-resident gd17 T cells, we characterized the nearest central nervous system (CNS)-associated source of IL-17a under homeostasis. Meningeal gd T cell-derived IL-17a was associated with anxiety-like behaviors in mice, which partially depended on T-cell receptor engagement and commensal microbiota. IL-17a receptor was highly expressed in glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice by shaping the transcriptional landscape and synaptic transmission of neurons in the medial prefrontal cortex (mPFC). From an evolutionary perspective, these findings suggest that IL-17a production by tissue-resident meningeal gd17 T cells may represent an evolutionary bridge between conserved anti-pathogen molecules and avoidance/survival behavioral traits in vertebrates. 3 nuclei samples of 4 mice pooled after elevated plus maze task from SynCre:Il17rafl/fl, SynCre, and Il17ra fl/fl mice.