Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. [Display omitted] [Display omitted] •Residential CD4 T cells are present in the healthy mouse and human brain•Brain residency is a transient program initiated in situ and lasting weeks•CD4 T cell entry around birth drives a transcriptional maturation step in microglia•Absence of CD4 T cells results in defective synaptic pruning and behavior Identification of brain-resident CD4+ T cells in mice and humans, which are required for microglia maturation and proper synaptic pruning and behavior.