Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.
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Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature. / Kleinschnitz, Christoph; Kraft, Peter; Dreykluft, Angela; Hagedorn, Ina; Göbel, Kerstin; Schuhmann, Michael K; Langhauser, Friederike; Helluy, Xavier; Schwarz, Tobias; Bittner, Stefan; Mayer, Christian T; Brede, Marc; Varallyay, Csanad; Pham, Mirko; Bendszus, Martin; Jakob, Peter; Magnus, Tim; Meuth, Sven G; Iwakura, Yoichiro; Zernecke, Alma; Sparwasser, Tim; Nieswandt, Bernhard; Stoll, Guido; Wiendl, Heinz.
in: BLOOD, Jahrgang 121, Nr. 4, 4, 2013, S. 679-691.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature.
AU - Kleinschnitz, Christoph
AU - Kraft, Peter
AU - Dreykluft, Angela
AU - Hagedorn, Ina
AU - Göbel, Kerstin
AU - Schuhmann, Michael K
AU - Langhauser, Friederike
AU - Helluy, Xavier
AU - Schwarz, Tobias
AU - Bittner, Stefan
AU - Mayer, Christian T
AU - Brede, Marc
AU - Varallyay, Csanad
AU - Pham, Mirko
AU - Bendszus, Martin
AU - Jakob, Peter
AU - Magnus, Tim
AU - Meuth, Sven G
AU - Iwakura, Yoichiro
AU - Zernecke, Alma
AU - Sparwasser, Tim
AU - Nieswandt, Bernhard
AU - Stoll, Guido
AU - Wiendl, Heinz
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - Cell Communication
KW - Lymphocyte Depletion
KW - Adoptive Transfer
KW - Blood Platelets/immunology/metabolism
KW - Brain/immunology/metabolism/pathology
KW - Brain Ischemia/genetics/immunology/therapy
KW - Endothelial Cells/immunology/metabolism
KW - Microvessels/pathology/physiopathology
KW - Stroke/immunology/metabolism/therapy
KW - T-Lymphocytes, Regulatory/immunology/metabolism
KW - Animals
KW - Male
KW - Disease Models, Animal
KW - Mice
KW - Mice, Knockout
KW - Cell Communication
KW - Lymphocyte Depletion
KW - Adoptive Transfer
KW - Blood Platelets/immunology/metabolism
KW - Brain/immunology/metabolism/pathology
KW - Brain Ischemia/genetics/immunology/therapy
KW - Endothelial Cells/immunology/metabolism
KW - Microvessels/pathology/physiopathology
KW - Stroke/immunology/metabolism/therapy
KW - T-Lymphocytes, Regulatory/immunology/metabolism
U2 - 10.1182/blood-2012-04-426734
DO - 10.1182/blood-2012-04-426734
M3 - SCORING: Journal article
C2 - 23160472
VL - 121
SP - 679
EP - 691
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 4
M1 - 4
ER -
