The kallikrein-kinin system modulates CD4+ T cell function and contributes to T cell migration into the brain after stroke

Abstract Ischemic stroke elicits a sustained thromboinflammatory response that critically shapes secondary brain injury. The kallikrein-kinin system (KKS) has been identified as the interface of vascular injury and inflammatory processes; however, its role in adaptive immunity remains poorly defined. Here, we show that the KKS is associated with pathogenic CD4 + T cell activation and trafficking. In both ischemic stroke patients and mice subjected to transient middle cerebral artery occlusion (tMCAO), circulating CD4 + T cells exhibited a conserved, activated, and trafficking-competent phenotype characterized by upregulation of adhesion/migration markers, indicating a translationally preserved systemic adaptive immune response. Functionally, serum from stroke mice subacutely treated with a plasma kallikrein (PK)-neutralizing antibody (ɑPK) attenuated CD4 + T cell activation, proliferation, expression of adhesion/migration markers, and pro-inflammatory cytokine production in vitro. PK selectively enhanced CD4 + T cell adhesion and migration, while its downstream metabolite Des-Arg 9 -bradykinin (Des-Arg 9 -BK) induced a pronounced pro-inflammatory, pro-migratory phenotype and potentiated chemokine-driven transendothelial migration in vitro. Strikingly, delayed PK inhibition in vivo was associated with reduced T cell accumulation in the ischemic brain and increased circulating CD4 + T cell frequencies, suggesting impaired central nervous system (CNS) infiltration dynamics. Together, these findings support a role for KKS signaling in shaping neuroimmune interactions after ischemic stroke by enhancing endothelial adhesiveness and facilitating CD4 + T cell migration to the ischemic tissue. By linking thromboinflammation and adaptive immunity, the KKS emerges as a promising therapeutic target to selectively modulate neuroimmune interactions and potentially improve functional recovery after ischemic stroke.