Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature

Christoph Kleinschnitz, Peter Kraft, Angela Dreykluft, Ina Hagedorn, Kerstin Göbel, Michael K. Schuhmann, Friederike Langhauser, Xavier Helluy, Tobias Schwarz, Stefan Bittner, Christian T. Mayer, Marc Brede, Csanad Varallyay, Mirko Pham, Martin Bendszus, Peter Jakob, Tim Magnus, Sven G. Meuth, Yoichiro Iwakura, Alma Zernecke, Tim Sparwasser, Bernhard Nieswandt, Guido Stoll and Heinz Wiendl


We have recently identified T cells as important mediators of ischemic brain damage but the contribution of the different T cell subsets is unclear. Forkheadbox P3 (FoxP3)+ regulatory T lymphocytes (Treg) are generally regarded as prototypic anti-inflammatory cells that maintain immune tolerance and counteract tissue damage in a variety of immune-mediated disorders. We examined the role of Treg after experimental brain ischemia/reperfusion injury. Selective depletion of Treg in the DEREG mouse model dramatically reduced infarct size and improved neurological function 24h post 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 as well as Rag1-/- mice lacking lymphocytes. Mechanistically, Treg 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 could be confirmed in vitro. Ablation of Treg reduced microvascular thrombus formation and improved cerebral reperfusion upon stroke as revealed by ultrahigh-field magnetic resonance imaging at 17.6 Tesla. In contrast, established immunoregulatory characteristics of Treg had no functional relevance. We here define a novel and unexpected role of Treg in a primary non-immunological disease state.

  • Submitted April 26, 2012.
  • Accepted October 27, 2012.