Table of Contents Author Guidelines Submit a Manuscript
The Scientific World Journal
Volume 2013 (2013), Article ID 174373, 8 pages
http://dx.doi.org/10.1155/2013/174373
Review Article

The Paradox Role of Regulatory T Cells in Ischemic Stroke

Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 21002, China

Received 27 August 2013; Accepted 18 September 2013

Academic Editors: C. D. Jun and A. Varas

Copyright © 2013 Xiaomeng Xu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. R. Macrez, C. Ali, O. Toutirais et al., “Stroke and the immune system: from pathophysiology to new therapeutic strategies,” The Lancet Neurology, vol. 10, no. 5, pp. 471–480, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. Y. Jiang, N. Wei, T. Lu, J. Zhu, G. Xu, and X. Liu, “Intranasal brain-derived neurotrophic factor protects brain from ischemic insult via modulating local inflammation in rats,” Neuroscience, vol. 172, pp. 398–405, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. X. Liu, “Beyond the time window of intravenous thrombolysis: standing by or by stenting?” Interventional Neurology, vol. 1, no. 1, pp. 3–15, 2012. View at Publisher · View at Google Scholar
  4. G. Xu, M. Ma, X. Liu, and G. J. Hankey, “Is there a stroke belt in China and why?” Stroke, vol. 44, no. 7, pp. 1775–1783, 2013. View at Publisher · View at Google Scholar
  5. C. E. Downes and P. J. Crack, “Neural injury following stroke: are Toll-like receptors the link between the immune system and the CNS?” British Journal of Pharmacology, vol. 160, no. 8, pp. 1872–1888, 2010. View at Publisher · View at Google Scholar · View at Scopus
  6. Y. Jiang, J. Zhu, G. Xu, and X. Liu, “Intranasal delivery of stem cells to the brain,” Expert Opinion on Drug Delivery, vol. 8, no. 5, pp. 623–632, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. Á. Chamorro, A. Meisel, A. M. Planas, X. Urra, D. van de Beek, and R. Veltkamp, “The immunology of acute stroke,” Nature Reviews Neurology, vol. 8, no. 7, pp. 401–410, 2012. View at Google Scholar
  8. L. Steinman, “Elaborate interactions between the immune and nervous systems,” Nature Immunology, vol. 5, no. 6, pp. 575–581, 2004. View at Publisher · View at Google Scholar · View at Scopus
  9. W. R. Schabitz, “Regulatory T cells in ischemic stroke: helpful or hazardous?” Stroke, vol. 44, no. 8, p. e84, 2013. View at Publisher · View at Google Scholar
  10. Á. Chamorro and J. Hallenbeck, “The harms and benefits of inflammatory and immune responses in vascular disease,” Stroke, vol. 37, no. 2, pp. 291–293, 2006. View at Publisher · View at Google Scholar · View at Scopus
  11. T. Magnus, H. Wiendl, and C. Kleinschnitz, “Immune mechanisms of stroke,” Current Opinion in Neurology, vol. 25, no. 3, pp. 334–340, 2012. View at Publisher · View at Google Scholar
  12. A. M. Planas and A. Chamorro, “Regulatory T cells protect the brain after stroke,” Nature Medicine, vol. 15, no. 2, pp. 138–139, 2009. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Gelderblom, F. Leypoldt, K. Steinbach et al., “Temporal and spatial dynamics of cerebral immune cell accumulation in stroke,” Stroke, vol. 40, no. 5, pp. 1849–1857, 2009. View at Publisher · View at Google Scholar · View at Scopus
  14. P. D. Hurn, S. Subramanian, S. M. Parker et al., “T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation,” Journal of Cerebral Blood Flow and Metabolism, vol. 27, no. 11, pp. 1798–1805, 2007. View at Publisher · View at Google Scholar · View at Scopus
  15. C. Kleinschnitz and H. Wiendl, “CON: regulatory T cells are protective in ischemic stroke,” Stroke, vol. 44, no. 8, pp. e87–e88, 2013. View at Publisher · View at Google Scholar
  16. S. Sakaguchi, “Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses,” Annual Review of Immunology, vol. 22, pp. 531–562, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. S. Sakaguchi, T. Yamaguchi, T. Nomura, and M. Ono, “Regulatory T cells and immune tolerance,” Cell, vol. 133, no. 5, pp. 775–787, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. S. Hori, T. Nomura, and S. Sakaguchi, “Control of regulatory T cell development by the transcription factor Foxp3,” Science, vol. 299, no. 5609, pp. 1057–1061, 2003. View at Publisher · View at Google Scholar · View at Scopus
  19. S. Sakaguchi, M. Miyara, C. M. Costantino, and D. A. Hafler, “FOXP3 + regulatory T cells in the human immune system,” Nature Reviews Immunology, vol. 10, no. 7, pp. 490–500, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. R. K. Gershon and K. Kondo, “Cell interactions in the induction of tolerance: the role of thymic lymphocytes,” Immunology, vol. 18, no. 5, pp. 723–737, 1970. View at Google Scholar · View at Scopus
  21. S. Sakaguchi, N. Sakaguchi, M. Asano, M. Itoh, and M. Toda, “Immunologic self-tolerance maintained by activated T cells expressing IL- 2 receptor α-chains (CD25): breakdown of a single mechanism of self- tolerance causes various autoimmune diseases,” The Journal of Immunology, vol. 155, no. 3, pp. 1151–1164, 1995. View at Google Scholar · View at Scopus
  22. S. Sakaguchi, K. Wing, and M. Miyara, “Regulatory T cells—a brief history and perspective,” European Journal of Immunology, vol. 37, no. 1, pp. S116–S123, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. C. Baecher-Allan, J. A. Brown, G. J. Freeman, and D. A. Hafler, “CD4+ CD25high regulatory cells in human peripheral blood,” The Journal of Immunology, vol. 167, no. 3, pp. 1245–1253, 2001. View at Google Scholar · View at Scopus
  24. D. Dieckmann, H. Plottner, S. Berchtold, T. Berger, and G. Schuler, “Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood,” The Journal of Experimental Medicine, vol. 193, no. 11, pp. 1303–1310, 2001. View at Publisher · View at Google Scholar · View at Scopus
  25. M. K. Levings, R. Sangregorio, and M.-G. Roncarolo, “Human CD25+CD4+ T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function,” The Journal of Experimental Medicine, vol. 193, no. 11, pp. 1295–1302, 2001. View at Publisher · View at Google Scholar · View at Scopus
  26. K. J. Maloy and F. Powrie, “Regulatory T cells in the control of immune pathology,” Nature Immunology, vol. 2, no. 9, pp. 816–822, 2001. View at Publisher · View at Google Scholar · View at Scopus
  27. W. F. Ng, P. J. Duggan, F. Ponchel et al., “Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells,” Blood, vol. 98, no. 9, pp. 2736–2744, 2001. View at Publisher · View at Google Scholar · View at Scopus
  28. A. M. Thornton and E. M. Shevach, “CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production,” The Journal of Experimental Medicine, vol. 188, no. 2, pp. 287–296, 1998. View at Publisher · View at Google Scholar · View at Scopus
  29. D. C. Gondek, L.-F. Lu, S. A. Quezada, S. Sakaguchi, and R. J. Noelle, “Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism,” The Journal of Immunology, vol. 174, no. 4, pp. 1783–1786, 2005. View at Google Scholar · View at Scopus
  30. W. J. Grossman, J. W. Verbsky, B. L. Tollefsen, C. Kemper, J. P. Atkinson, and T. J. Ley, “Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells,” Blood, vol. 104, no. 9, pp. 2840–2848, 2004. View at Publisher · View at Google Scholar · View at Scopus
  31. W. J. Grossman, J. W. Verbsky, W. Barchet, M. Colonna, J. P. Atkinson, and T. J. Ley, “Human T regulatory cells can use the perforin pathway to cause autologous target cell death,” Immunity, vol. 21, no. 4, pp. 589–601, 2004. View at Publisher · View at Google Scholar · View at Scopus
  32. X. Cao, S. F. Cai, T. A. Fehniger et al., “Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance,” Immunity, vol. 27, no. 4, pp. 635–646, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. S. Deaglio, K. M. Dwyer, W. Gao et al., “Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression,” The Journal of Experimental Medicine, vol. 204, no. 6, pp. 1257–1265, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. G. Borsellino, M. Kleinewietfeld, D. Di Mitri et al., “Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression,” Blood, vol. 110, no. 4, pp. 1225–1232, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. J. J. Kobie, P. R. Shah, L. Yang, J. A. Rebhahn, D. J. Fowell, and T. R. Mosmann, “T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine,” The Journal of Immunology, vol. 177, no. 10, pp. 6780–6786, 2006. View at Google Scholar · View at Scopus
  36. T. Bopp, C. Becker, M. Klein et al., “Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression,” The Journal of Experimental Medicine, vol. 204, no. 6, pp. 1303–1310, 2007. View at Publisher · View at Google Scholar · View at Scopus
  37. P. Serra, A. Amrani, J. Yamanouchi et al., “CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells,” Immunity, vol. 19, no. 6, pp. 877–889, 2003. View at Publisher · View at Google Scholar · View at Scopus
  38. C. E. Tadokoro, G. Shakhar, S. Shen et al., “Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo,” The Journal of Experimental Medicine, vol. 203, no. 3, pp. 505–511, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. F. Fallarino, U. Grohmann, K. W. Hwang et al., “Modulation of tryptophan catabolism by regulatory T cells,” Nature Immunology, vol. 4, no. 12, pp. 1206–1212, 2003. View at Publisher · View at Google Scholar · View at Scopus
  40. D. A. A. Vignali, L. W. Collison, and C. J. Workman, “How regulatory T cells work,” Nature Reviews Immunology, vol. 8, no. 7, pp. 523–532, 2008. View at Publisher · View at Google Scholar · View at Scopus
  41. T. Takahashi, Y. Kuniyasu, M. Toda et al., “Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state,” International Immunology, vol. 10, no. 12, pp. 1969–1980, 1998. View at Google Scholar · View at Scopus
  42. E. M. Shevach, “From vanilla to 28 flavors: multiple varieties of T regulatory cells,” Immunity, vol. 25, no. 2, pp. 195–201, 2006. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Wigren, H. Björkbacka, L. Andersson et al., “Low levels of circulating CD4+FoxP3+ T cells are associated with an increased risk for development of myocardial infarction but not for stroke,” Arteriosclerosis Thrombosis and Vascular Biology, vol. 32, no. 8, pp. 2000–2007, 2012. View at Google Scholar
  44. G. K. Hansson, “Atherosclerosis—an immune disease. The anitschkov lecture 2007,” Atherosclerosis, vol. 202, no. 1, pp. 2–10, 2009. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Kassan, A. Wecker, P. Kadowitz, M. Trebak, and K. Matrougui, “CD4+CD25+Foxp3 regulatory T cells and vascular dysfunction in hypertension,” Journal of Hypertension, vol. 31, no. 10, pp. 1939–1943, 2013. View at Google Scholar
  46. H. Offner, S. Subramanian, S. M. Parker et al., “Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages,” The Journal of Immunology, vol. 176, no. 11, pp. 6523–6531, 2006. View at Google Scholar · View at Scopus
  47. X. Urra, Á. Cervera, N. Villamor, A. M. Planas, and Á. Chamorro, “Harms and benefits of lymphocyte subpopulations in patients with acute stroke,” Neuroscience, vol. 158, no. 3, pp. 1174–1183, 2009. View at Publisher · View at Google Scholar · View at Scopus
  48. J. Yan, S. J. Read, R. D. Henderson et al., “Frequency and function of regulatory T cells after ischaemic stroke in humans,” Journal of Neuroimmunology, vol. 243, no. 1-2, pp. 89–94, 2012. View at Publisher · View at Google Scholar · View at Scopus
  49. H. A. Seifert, A. A. Hall, C. B. Chapman, L. A. Collier, A. E. Willing, and K. R. Pennypacker, “A transient decrease in spleen size following stroke corresponds to splenocyte release into systemic circulation,” Journal of Neuroimmune Pharmacology, vol. 7, no. 4, pp. 1017–1024, 2012. View at Google Scholar
  50. C. Kleinschnitz, P. Kraft, A. Dreykluft et al., “Regulatory T cells are strong promoters of acute ischemic stroke in mice by inducing dysfunction of the cerebral microvasculature,” Blood, vol. 121, no. 4, pp. 679–691, 2013. View at Publisher · View at Google Scholar
  51. P. Li, Y. Gan, B. L. Sun et al., “Adoptive regulatory T-cell therapy protects against cerebral ischemia,” Annals of Neurology, 2012. View at Publisher · View at Google Scholar
  52. T. Stubbe, F. Ebner, D. Richter et al., “Regulatory T cells accumulate and proliferate in the ischemic hemisphere for up to 30 days after MCAO,” Journal of Cerebral Blood Flow and Metabolism, vol. 33, no. 1, pp. 37–47, 2013. View at Google Scholar
  53. X. Hu, P. Li, and J. Chen, “PRO: regulatory T cells are protective in ischemic stroke,” Stroke, vol. 44, no. 8, pp. e85–e86, 2013. View at Google Scholar
  54. H. Ait-Oufella, B. L. Salomon, S. Potteaux et al., “Natural regulatory T cells control the development of atherosclerosis in mice,” Nature Medicine, vol. 12, no. 2, pp. 178–180, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. A. Liesz, E. Suri-Payer, C. Veltkamp et al., “Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke,” Nature Medicine, vol. 15, no. 2, pp. 192–199, 2009. View at Publisher · View at Google Scholar · View at Scopus
  56. K. Matsumoto, M. Ogawa, J.-I. Suzuki, Y. Hirata, R. Nagai, and M. Isobe, “Regulatory T lymphocytes attenuate myocardial infarction-induced ventricular remodeling in mice,” International Heart Journal, vol. 52, no. 6, pp. 382–387, 2011. View at Publisher · View at Google Scholar · View at Scopus
  57. L. Lu, G. Li, J. Rao et al., “In vitro induced CD4+CD25+Foxp3+ Tregs attenuate hepatic ischemia-reperfusion injury,” International Immunopharmacology, vol. 9, no. 5, pp. 549–552, 2009. View at Publisher · View at Google Scholar · View at Scopus
  58. D. A. Ferenbach, D. C. Kluth, and J. Hughes, “Regulatory T cells: a brake on ischemic injury or an active promoter of tissue healing,” Kidney International, vol. 76, no. 7, pp. 689–691, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. C. Iadecola and J. Anrather, “The immunology of stroke: from mechanisms to translation,” Nature Medicine, vol. 17, no. 7, pp. 796–808, 2011. View at Publisher · View at Google Scholar · View at Scopus
  60. X. Ren, K. Akiyoshi, A. A. Vandenbark, P. D. Hurn, and H. Offner, “CD4+FoxP3+ regulatory T-cells in cerebral ischemic stroke,” Metabolic Brain Disease, vol. 26, no. 1, pp. 87–90, 2011. View at Publisher · View at Google Scholar · View at Scopus
  61. L. Gu, X. Xiong, H. Zhang, B. Xu, G. K. Steinberg, and H. Zhao, “Distinctive effects of T cell subsets in neuronal injury induced by cocultured splenocytes in vitro and by in vivo stroke in mice,” Stroke, vol. 43, no. 7, pp. 1941–1946, 2012. View at Google Scholar