CD4+ T cells in the developing human brain shape angiogenesis and neurogenesis

Although entry is limited, immune cells reside within and influence neural tissue function in health and disease. Unique T cell populations throughout the body may shape organogenesis, but these cells are absent during mouse embryogenesis. To investigate human prenatal T cell roles, we captured T cells from four midgestation organs: spleen, mesenteric lymph node, small intestine, and brain. Single-cell RNA sequencing identified dominant CD4 populations and smaller subsets of cytotoxic CD8 and innate T cells. In the brain, distinct expression profiles were revealed, including a unique Trav1-2+ MAIT-like population. Spatial mapping showed T cells are predominantly localized within the ventricular angiogenic-neurogenic niche, adjacent to microglia. Functionally, co-culture of CD4 T cells and endothelial cells enhanced vascular network maturity, while transplanted CD4 T cells in brain organoids localized to the VZ niche and reduced cell death. Rag2 knock-out mice also show changes in brain vasculature and neuronal structure in the absence of B and T cells. These findings suggest T cells support tissue health and growth in the developing human brain and have implications for neurodevelopment in a growing population of surviving patients with immunodeficiency syndromes.