Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Christoph Kleinschnitz1,*,
  2. Peter Kraft1,
  3. Angela Dreykluft1,
  4. Ina Hagedorn2,
  5. Kerstin Göbel3,
  6. Michael K. Schuhmann3,
  7. Friederike Langhauser1,
  8. Xavier Helluy4,
  9. Tobias Schwarz1,
  10. Stefan Bittner3,
  11. Christian T. Mayer5,
  12. Marc Brede6,
  13. Csanad Varallyay7,
  14. Mirko Pham8,
  15. Martin Bendszus8,
  16. Peter Jakob4,
  17. Tim Magnus9,
  18. Sven G. Meuth10,
  19. Yoichiro Iwakura11,
  20. Alma Zernecke2,
  21. Tim Sparwasser5,
  22. Bernhard Nieswandt12,
  23. Guido Stoll1, and
  24. Heinz Wiendl3
  1. 1 University of Wuerzburg, Department of Neurology, Wuerzburg, Germany;
  2. 2 University of Wuerzburg, Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, Wuerzburg, Germany;
  3. 3 University of Muenster, Department of Neurology - Inflammatory Disorders of the Nervous System and Neurooncology, Muenster, Germany;
  4. 4 University of Wuerzburg, Department of Experimental Physics, Section V, Wuerzburg, Germany;
  5. 5 Institute of Infection Immunology, TWINCORE, Center for Experimental and Clinical Infection Research, a joint venture between the Medical School Hannover and the Helmholtz Centre for Infection Research, Hannover, Germany;
  6. 6 University of Wuerzburg, Dept. of Anesthesiology and Critical Care, Wuerzburg, Germany;
  7. 7 University of Wuerzburg, Dept. of Neuroradiology, Wuerzburg, Germany;
  8. 8 University of Heidelberg, Dept. of Neuroradiology, Heidelberg, Germany;
  9. 9 University Hospital Hamburg-Eppendorf, Department of Neurology, Hamburg, Germany;
  10. 10 University of Muenster, Institute of Physiology - Neuropathophysiology, Muenster, Germany;
  11. 11 Institute of Medical Science, The University of Tokyo, Tokyo, Japan;
  12. 12 University Hospital Wuerzburg, Chair of Vascular Medicine, Wuerzburg, Germany
  1. * Corresponding author; email: christoph.kleinschnitz{at}


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.