CD4 T lymphocytes shape the development and maturation of the central nervous system

For decades, the central nervous system (CNS) was considered largely isolated from the peripheral immune system. However, growing evidence indicates that adaptive immune cells contribute to neurodevelopment and brain homeostasis. T lymphocytes are present in healthy brain parenchyma and have been implicated in microglial maturation and behavioral regulation, although their precise roles remain incompletely understood. Here, we aimed to identify and localize T lymphocytes in the brain parenchyma across developmental stages and to evaluate the contribution of CD4⁺ T cell subpopulations to mouse behavior. We detected T lymphocytes in multiple brain regions at different ages, with a predominance of CD4⁺ over CD8⁺ T lymphocytes from postnatal day 7 through 20 months. During the neonatal period, naïve T cells were more prevalent, whereas effector memory T cells increased progressively with age. Behavioral assessment of immunodeficient neonates and adults revealed neuromotor and cognitive alterations. Together, these findings indicate that T lymphocytes are associated with brain maturation and cognitive-related outcomes, highlighting a potential influence of adaptive immunity on neural development.