The kallikrein-kinin system (KKS) shapes neuroimmune interactions after ischemic stroke by enhancing endothelial adhesiveness and facilitating CD4+ T cell migration to ischemic tissue, emerging as a promising therapeutic target to selectively modulate neuroimmune interactions and potentially improve functional recovery.
Key Findings
Results
Circulating CD4+ T cells in both ischemic stroke patients and tMCAO mice displayed a conserved activated and trafficking-competent phenotype.
CD4+ T cells showed upregulation of adhesion and migration markers in both human stroke patients and mice subjected to transient middle cerebral artery occlusion (tMCAO)
This phenotype was described as 'translationally preserved,' indicating conservation across species
The activated phenotype was characterized as indicating a 'systemic adaptive immune response'
Findings were observed in both clinical (human stroke patients) and preclinical (mouse tMCAO model) settings
Results
Serum from stroke mice treated with a plasma kallikrein (PK)-neutralizing antibody attenuated multiple CD4+ T cell activation parameters in vitro.
Treatment was described as 'subacute' administration of a plasma kallikrein-neutralizing antibody (αPK)
The αPK treatment attenuated CD4+ T cell activation, proliferation, expression of adhesion/migration markers, and pro-inflammatory cytokine production
Effects were demonstrated in vitro using serum from αPK-treated stroke mice
These findings implicate PK-mediated signaling in driving the systemic CD4+ T cell activation response following stroke
Results
Plasma kallikrein (PK) selectively enhanced CD4+ T cell adhesion and migration in vitro.
PK selectively enhanced CD4+ T cell adhesion and migration
The effect was selective for CD4+ T cells, suggesting a cell-type-specific mechanism
These experiments were conducted in vitro
The finding links PK activity directly to pro-migratory behavior of CD4+ T cells
Results
Des-Arg9-bradykinin (Des-Arg9-BK), a downstream KKS metabolite, induced a pronounced pro-inflammatory and pro-migratory CD4+ T cell phenotype and potentiated chemokine-driven transendothelial migration.
Des-Arg9-BK is described as a downstream metabolite of PK
Treatment induced a 'pronounced pro-inflammatory, pro-migratory phenotype' in CD4+ T cells
Des-Arg9-BK potentiated chemokine-driven transendothelial migration in vitro
This suggests a two-component KKS mechanism where both PK and its metabolite Des-Arg9-BK contribute to CD4+ T cell trafficking
Results
Delayed PK inhibition in vivo was associated with reduced T cell accumulation in the ischemic brain and increased circulating CD4+ T cell frequencies.
In vivo treatment with the PK-neutralizing antibody was administered in a delayed fashion after stroke
PK inhibition was associated with reduced T cell accumulation in the ischemic brain
Simultaneously, increased circulating CD4+ T cell frequencies were observed, suggesting impaired CNS infiltration dynamics
The authors interpreted these findings as indicating that KKS signaling facilitates CD4+ T cell migration into the ischemic CNS
Background
The kallikrein-kinin system represents an interface between thromboinflammation and adaptive immunity in the context of ischemic stroke.
The KKS has been identified as 'the interface of vascular injury and inflammatory processes'
Prior to this work, its role in adaptive immunity was described as 'poorly defined'
The study links KKS-mediated thromboinflammation to CD4+ T cell activation and CNS trafficking
The KKS is described as 'a promising therapeutic target to selectively modulate neuroimmune interactions and potentially improve functional recovery after ischemic stroke'
What This Means
This research suggests that a biological signaling system called the kallikrein-kinin system (KKS) — best known for its role in blood clotting and inflammation — also plays an important role in directing immune cells called CD4+ T cells into the brain after a stroke. After a stroke, the brain can be further damaged by inflammation, and immune cells that infiltrate the injured brain tissue are thought to contribute to this secondary damage. The researchers found that both stroke patients and stroke mice had similar patterns of CD4+ T cell activation, suggesting that findings in mice may be relevant to human disease.
Using laboratory experiments, the team showed that a key KKS protein called plasma kallikrein (PK) directly encouraged CD4+ T cells to stick to blood vessel walls and migrate, and that one of its breakdown products (Des-Arg9-bradykinin) further amplified this pro-inflammatory and migratory behavior, including helping T cells cross the blood-brain barrier. Importantly, when they blocked PK activity in stroke mice using a neutralizing antibody, fewer T cells accumulated in the ischemic brain region and more remained in circulation — consistent with reduced migration into the brain.
This research suggests that the KKS acts as a bridge connecting blood clotting and vascular injury responses to the adaptive immune system, specifically by promoting harmful CD4+ T cell trafficking into injured brain tissue after stroke. Targeting the KKS — for example, with a PK-blocking antibody — could potentially reduce this immune-driven secondary brain injury, pointing toward a new therapeutic strategy for improving stroke recovery. The fact that the immune cell activation patterns were similar in both humans and mice strengthens the potential clinical relevance of these findings.
Gausmann N, Haupeltshofer S, Szepanowski R, Luppus S, Dzyubenko E, Bahr J, et al.. (2026). The kallikrein-kinin system modulates CD4+ T cell function and contributes to T cell migration into the brain after stroke.. Journal of neuroinflammation. https://doi.org/10.1186/s12974-026-04034-4