Adaptive immune signals shape neural circuit development through CNS Border-Glia pathways.

The central nervous system (CNS) has long been considered a relatively immune-privileged site. However, accumulating evidence indicates that CNS border structures, including the meninges, choroid plexus, blood-brain barrier (BBB), and perivascular spaces, are not merely passive barriers but dynamic immune interfaces that enable regulated communication between the peripheral immune system and the brain microenvironment. This review discusses how adaptive immune signals are filtered, integrated, and translated at CNS borders during critical developmental windows, and how these signals subsequently influence neural circuit development through microglia and astrocytes. Meningeal-resident T cells, B cells, plasma cells, and related innate-like lymphocytes can establish cytokine milieus characterized by IL-4, IL-17 A, IFN-γ, and other immune mediators within border niches. Once sensed by glial cells, these signals can regulate complement-dependent synaptic pruning, receptor-mediated phagocytosis, astrocyte-derived synaptic homeostatic factors, and excitatory/inhibitory (E/I) balance. Because glial cells exhibit marked heterogeneity across brain regions and developmental stages, the same immune bias may produce time-window-dependent and region-specific neurodevelopmental consequences. These processes do not usually determine the onset of a specific disease directly; rather, they reshape developmental trajectories of neural circuits and thereby alter susceptibility to neurodevelopmental and neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Overall, this review highlights glial cells as pivotal cellular hubs linking adaptive immunity, CNS border microenvironments, and neural circuit development, and provides a mechanistic framework for understanding neuroimmune interactions and their translational relevance.