Targeting CD4⁺ T cell infiltration: mechanisms and therapeutic insights into CD4⁺ T cell transmigration across the blood–brain barrier in acute ischemic stroke

Abstract The blood-brain barrier (BBB) serves as a physical barrier of the central nervous system, characterized by selective permeability and immune isolation. It plays a critical role in transporting essential nutrients for normal neuronal metabolism while preventing the entry of toxic substances into the brain. Following acute ischemic stroke, the integrity of the BBB is compromised, leading to extensive T-cell infiltration into the brain. These infiltrating T cells influence BBB permeability and can exert either protective or detrimental effects on brain tissue. Current research has largely focused on the subset-specific regulation of T cells after their infiltration or on inhibiting T-cell migration into the brain during ischemic stroke. However, a systematic understanding of the routes and mechanisms underlying T-cell trafficking across the BBB in this context remains limited. In this review, we systematically examine the functional alterations of the BBB induced by different CD4 + T-cell subsets in ischemic stroke and explore the associated molecular mechanisms. Special emphasis is placed on the migratory behavior of CD4 + T cells across the BBB, highlighting the roles of selectins, LFA-1, ICAM, and VCAM in mediating T-cell capture, adhesion, and transmigration. We also provide a detailed discussion of immunosuppressive agents clinically used to inhibit the infiltration of peripheral immune cells into the brain. By synthesizing these insights, this review aims to inform the optimization of therapeutic strategies targeting CD4 + T-cell trafficking and to facilitate the development of adjunct neuroprotective approaches, thereby advancing stroke treatment and improving patient outcomes. Ultimately, this work seeks to deepen the understanding of the mechanisms by which CD4 + T cells influence ischemic stroke and to provide a theoretical foundation for novel immunomodulatory neuroprotective therapies.