title: Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.
abstract: We have recently identified T cells as important mediators of ischemic brain damage, but the contribution of the different T-cell subsets is unclear. Forkhead box P3 (FoxP3)-positive regulatory T cells (Tregs) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. In the present study, we examined the role of Tregs after experimental brain ischemia/reperfusion injury. Selective depletion of Tregs in the DEREG mouse model dramatically reduced infarct size and improved neurologic function 24 hours after stroke and this protective effect was preserved at later stages of infarct development. The specificity of this detrimental Treg effect was confirmed by adoptive transfer experiments in wild-type mice and in Rag1(-/-) mice lacking lymphocytes. Mechanistically, Tregs induced microvascular dysfunction in vivo by increased interaction with the ischemic brain endothelium via the LFA-1/ICAM-1 pathway and platelets and these findings were confirmed in vitro. Ablation of Tregs reduced microvascular thrombus formation and improved cerebral reperfusion on stroke, as revealed by ultra-high-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Tregs had no functional relevance. We define herein a novel and unexpected role of Tregs in a primary nonimmunologic disease state.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany. christoph.kleinschnitz@uni-wuerzburg.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Angela
authors.initials: A
authors.lastname: Dreykluft
authors.forename: Ina
authors.initials: I
authors.lastname: Hagedorn
authors.forename: Kerstin
authors.initials: K
authors.lastname: Göbel
authors.forename: Michael K
authors.initials: MK
authors.lastname: Schuhmann
authors.forename: Friederike
authors.initials: F
authors.lastname: Langhauser
authors.forename: Xavier
authors.initials: X
authors.lastname: Helluy
authors.forename: Tobias
authors.initials: T
authors.lastname: Schwarz
authors.forename: Stefan
authors.initials: S
authors.lastname: Bittner
authors.forename: Christian T
authors.initials: CT
authors.lastname: Mayer
authors.forename: Marc
authors.initials: M
authors.lastname: Brede
authors.forename: Csanad
authors.initials: C
authors.lastname: Varallyay
authors.forename: Mirko
authors.initials: M
authors.lastname: Pham
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.forename: Peter
authors.initials: P
authors.lastname: Jakob
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.forename: Sven G
authors.initials: SG
authors.lastname: Meuth
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
authors.forename: Tim
authors.initials: T
authors.lastname: Sparwasser
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.forename: Heinz
authors.initials: H
authors.lastname: Wiendl
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D002450:Cell Communication; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055806:Microvessels / Q000473:pathology / Q000503:physiopathology*; D020521:Stroke / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*