CXCL16-mediated recruitment of γδ T cells to the brain reduces sociability in mice

Autism spectrum disorder (ASD) is a neurodevelopmental disorder shaped by genetic factors such as copy number variations (CNVs) and immunological factors such as maternal infection. However, most studies on the development of genetic ASD have focused on neurological aspects, and the role of immunity in genetic ASD remains unclear. Here, we demonstrate increased γδ T cells in the brains of 15q11-13 duplication ( 15q dup ) mice, which model a common CNV associated with ASD. Elevated CXCL16 in the brains of 15q dup mice promoted γδ T cell infiltration, specifically of Vγ6 ⁺ γδ T cells that produce IL-17A. Deletion of Vγ6 ⁺ γδ T cells throughout development or treatment with neutralizing antibodies against Vγ6 or IL-17A increased social behavior in 15q dup mice. These findings suggest that immune dysregulation contributes to social behavior deficits in 15q dup mice, consistent with observations in maternal immune activation models, and may represent a potential target for interventions for ASD-associated differences in social behavior.