Abstract: Loss of immune tolerance to central nervous system (CNS) antigens lies at the heart of multiple sclerosis (MS), the most common chronic autoimmune disease of the CNS. MS affects nearly 2 million people worldwide and is characterized by focal areas of demyelination, inflammation, axonal injury, and neurodegeneration (Bronge et al., 2022; Magliozzi et al., 2023). The condition leads to symptoms such as numbness, muscle weakness, fatigue, visual impairment, and cognitive decline (Magliozzi et al., 2023). Although autoreactive T cells are considered to be primed in peripheral lymphoid tissues initially, it is the local reactivation of these T cells upon encountering CNS antigens that critically drives the inflammatory response within the CNS (Koch et al., 2022). It has become increasingly apparent that brain barriers, such as the blood–brain barrier (BBB), the blood– cerebrospinal fluid barrier (BCSFB), and the meninges, are central to modulating the immune response and driving MS pathology, potentially by facilitating antigen presentation and thus T cell reactivation (Ampie and McGavern, 2022; Magliozzi et al., 2023; Zierfuss et al., 2024). In this perspective, we examine current evidence on how antigen presentation occurs at major brain barrier sites and their contribution to triggering MS onset and progression.