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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\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation and trafficking. In both ischemic stroke patients and mice subjected to transient middle cerebral artery occlusion (tMCAO), circulating CD4\n                    <jats:sup>+<\/jats:sup>\n                    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 (\u0251PK) attenuated CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation, proliferation, expression of adhesion\/migration markers, and pro-inflammatory cytokine production in vitro. PK selectively enhanced CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell adhesion and migration, while its downstream metabolite Des-Arg\n                    <jats:sup>9<\/jats:sup>\n                    -bradykinin (Des-Arg\n                    <jats:sup>9<\/jats:sup>\n                    -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\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1186\/s12974-026-04034-4","type":"journal-article","created":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T03:05:22Z","timestamp":1788577522000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The kallikrein-kinin system modulates CD4+ T cell function and contributes to T cell migration into the brain after stroke"],"prefix":"10.1186","volume":"23","author":[{"given":"Nadine","family":"Gausmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Haupeltshofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca D.","family":"Szepanowski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sina","family":"Luppus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Egor","family":"Dzyubenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Bahr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stine","family":"Mencl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine","family":"Gronewold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk M.","family":"Hermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Forsting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelius","family":"Deuschl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Buer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid M.","family":"Westendorf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Kleinschnitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana I.","family":"Casas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Hansen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,5]]},"reference":[{"key":"4034_CR1","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1177\/17474930241308142","volume":"20","author":"VL Feigin","year":"2025","unstructured":"Feigin VL, Brainin M, Norrving B, Martins SO, Pandian J, Lindsay P, et al. 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All participants or their legal representatives provided written informed consent prior to inclusion. Sample collection and handling were performed in accordance with the Declaration of Helsinki and institutional guidelines for human biomedical research.The study was approved by the regional government authorities (Landesamt f\u00fcr Natur, Umwelt und Verbraucherschutz NRW, LANUV) and guided by the German Welfare Act (German Ministry of Agriculture, Health, and Economic Cooperation).","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"296"}}