Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke


Systemic and local inflammatory processes have a key, mainly detrimental role in the pathophysiology of ischemic stroke. Currently, little is known about endogenous counterregulatory immune mechanisms. We examined the role of the key immunomodulators CD4+CD25+ forkhead box P3 (Foxp3)+ regulatory T lymphocytes (Treg cells), after experimental brain ischemia. Depletion of Treg cells profoundly increased delayed brain damage and deteriorated functional outcome. Absence of Treg cells augmented postischemic activation of resident and invading inflammatory cells including microglia and T cells, the main sources of deleterious cerebral tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), respectively. Early antagonization of TNF-α and delayed neutralization of IFN-γ prevented infarct growth in Treg cell–depleted mice. Intracerebral interleukin-10 (IL-10) substitution abrogated the cytokine overexpression after Treg cell depletion and prevented secondary infarct growth, whereas transfer of IL-10–deficient Treg cells in an adoptive transfer model was ineffective. In conclusion, Treg cells are major cerebroprotective modulators of postischemic inflammatory brain damage targeting multiple inflammatory pathways. IL-10 signaling is essential for their immunomodulatory effect.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Treg cell depletion exacerbates ischemic lesion size and behavioral outcome.
Figure 2: Proinflammatory cytokine expression is elevated in the ischemic brain after Treg cell depletion, and their intracerebral antagonization reduces lesion size.
Figure 3: Treg cells reduce the early invasion of neutrophils into the brain and the activation of invading T cells.
Figure 4: Microglia are activated after ischemia, are the main source of cerebral TNF-α and are more abundant in brains of Treg cell–depleted mice.
Figure 5: Blood cytokine concentrations after MCAO.
Figure 6: Treg cell–derived IL-10 is the main mediator of the Treg cells' cerebroprotective effect.


  1. 1

    Donnan, G.A., Fisher, M., Macleod, M. & Davis, S.M. Stroke. Lancet 371, 1612–1623 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Lo, E.H., Dalkara, T. & Moskowitz, M.A. Mechanisms, challenges and opportunities in stroke. Nat. Rev. Neurosci. 4, 399–415 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Dirnagl, U. Inflammation in stroke: the good, the bad, and the unknown. Ernst Schering Res. Found. Workshop. 47, 87–99 (2004).

    Google Scholar 

  4. 4

    Wang, Q., Tang, X.N. & Yenari, M.A. The inflammatory response in stroke. J. Neuroimmunol. 184, 53–68 (2007).

    CAS  Article  Google Scholar 

  5. 5

    Arumugam, T.V., Granger, D.N. & Mattson, M.P. Stroke and T cells. Neuromolecular Med. 7, 229–242 (2005).

    CAS  Article  Google Scholar 

  6. 6

    Perera, M.N. et al. Inflammation following stroke. J. Clin. Neurosci. 13, 1–8 (2006).

    CAS  Article  Google Scholar 

  7. 7

    Meisel, C., Schwab, J.M., Prass, K., Meisel, A. & Dirnagl, U. Central nervous system injury-induced immune deficiency syndrome. Nat. Rev. Neurosci. 6, 775–786 (2005).

    CAS  Article  Google Scholar 

  8. 8

    Gee, J.M., Kalil, A., Shea, C. & Becker, K.J. Lymphocytes: potential mediators of postischemic injury and neuroprotection. Stroke 38, 783–788 (2007).

    Article  Google Scholar 

  9. 9

    McGeachy, M.J., Stephens, L.A. & Anderton, S.M. Natural recovery and protection from autoimmune encephalomyelitis: contribution of CD4+CD25+ regulatory cells within the central nervous system. J. Immunol. 175, 3025–3032 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Suri-Payer, E. & Fritzsching, B. Regulatory T cells in experimental autoimmune disease. Springer Semin. Immunopathol. 28, 3–16 (2006).

    CAS  Article  Google Scholar 

  11. 11

    Sakaguchi, S. et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212, 8–27 (2006).

    CAS  Article  Google Scholar 

  12. 12

    O'Connor, R.A. & Anderton, S.M. Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J. Neuroimmunol. 193, 1–11 (2008).

    CAS  Article  Google Scholar 

  13. 13

    O'Garra, A. & Vieira, P. Regulatory T cells and mechanisms of immune system control. Nat. Med. 10, 801–805 (2004).

    CAS  Article  Google Scholar 

  14. 14

    Tang, Q. & Bluestone, J.A. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat. Immunol. 9, 239–244 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Spera, P.A., Ellison, J.A., Feuerstein, G.Z. & Barone, F.C. IL-10 reduces rat brain injury following focal stroke. Neurosci. Lett. 251, 189–192 (1998).

    CAS  Article  Google Scholar 

  16. 16

    Gee, J.M., Kalil, A., Thullbery, M. & Becker, K.J. Induction of immunologic tolerance to myelin basic protein prevents central nervous system autoimmunity and improves outcome after stroke. Stroke 39, 1575–1582 (2008).

    Article  Google Scholar 

  17. 17

    Offner, H. et al. Splenic atrophy in experimental stroke is accompanied by increased regulatory T cells and circulating macrophages. J. Immunol. 176, 6523–6531 (2006).

    CAS  Article  Google Scholar 

  18. 18

    McNeill, A., Spittle, E. & Backstrom, B.T. Partial depletion of CD69-expressing natural regulatory T cells with the anti-CD25 monoclonal antibody PC61. Scand. J. Immunol. 65, 63–69 (2007).

    CAS  Article  Google Scholar 

  19. 19

    Schallert, T., Fleming, S.M., Leasure, J.L., Tillerson, J.L. & Bland, S.T. CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology 39, 777–787 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Zhang, L. et al. A test for detecting long-term sensorimotor dysfunction in the mouse after focal cerebral ischemia. J. Neurosci. Methods 117, 207–214 (2002).

    Article  Google Scholar 

  21. 21

    Barone, F.C. et al. Tumor necrosis factor-α. A mediator of focal ischemic brain injury. Stroke 28, 1233–1244 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Yilmaz, G., Arumugam, T.V., Stokes, K.Y. & Granger, D.N. Role of T lymphocytes and interferon-γ in ischemic stroke. Circulation 113, 2105–2112 (2006).

    Article  Google Scholar 

  23. 23

    Lambertsen, K.L. et al. A role for interferon-γ in focal cerebral ischemia in mice. J. Neuropathol. Exp. Neurol. 63, 942–955 (2004).

    CAS  Article  Google Scholar 

  24. 24

    Lambertsen, K.L., Meldgaard, M., Ladeby, R. & Finsen, B. A quantitative study of microglial-macrophage synthesis of tumor necrosis factor during acute and late focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 25, 119–135 (2005).

    CAS  Article  Google Scholar 

  25. 25

    Rothwell, N.J. & Luheshi, G.N. Interleukin 1 in the brain: biology, pathology and therapeutic target. Trends Neurosci. 23, 618–625 (2000).

    CAS  Article  Google Scholar 

  26. 26

    Gregersen, R., Lambertsen, K. & Finsen, B. Microglia and macrophages are the major source of tumor necrosis factor in permanent middle cerebral artery occlusion in mice. J. Cereb. Blood Flow Metab. 20, 53–65 (2000).

    CAS  Article  Google Scholar 

  27. 27

    Ito, D., Tanaka, K., Suzuki, S., Dembo, T. & Fukuuchi, Y. Enhanced expression of Iba1, ionized calcium-binding adapter molecule 1, after transient focal cerebral ischemia in rat brain. Stroke 32, 1208–1215 (2001).

    CAS  Article  Google Scholar 

  28. 28

    Offner, H. et al. Experimental stroke induces massive, rapid activation of the peripheral immune system. J. Cereb. Blood Flow Metab. 26, 654–665 (2006).

    CAS  Article  Google Scholar 

  29. 29

    Grilli, M. et al. Interleukin-10 modulates neuronal threshold of vulnerability to ischaemic damage. Eur. J. Neurosci. 12, 2265–2272 (2000).

    CAS  Article  Google Scholar 

  30. 30

    del Zoppo, G.J., Becker, K.J. & Hallenbeck, J.M. Inflammation after stroke: is it harmful? Arch. Neurol. 58, 669–672 (2001).

    CAS  Article  Google Scholar 

  31. 31

    Dirnagl, U., Iadecola, C. & Moskowitz, M.A. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci. 22, 391–397 (1999).

    CAS  Article  Google Scholar 

  32. 32

    del Zoppo, G. et al. Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol. 10, 95–112 (2000).

    CAS  Article  Google Scholar 

  33. 33

    Chamorro, A., Urra, X. & Planas, A.M. Infection after acute ischemic stroke: a manifestation of brain-induced immunodepression. Stroke 38, 1097–1103 (2007).

    Article  Google Scholar 

  34. 34

    Prass, K. et al. Stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1–like immunostimulation. J. Exp. Med. 198, 725–736 (2003).

    CAS  Article  Google Scholar 

  35. 35

    Planas, A.M., Gorina, R. & Chamorro, A. Signalling pathways mediating inflammatory responses in brain ischaemia. Biochem. Soc. Trans. 34, 1267–1270 (2006).

    CAS  Article  Google Scholar 

  36. 36

    Hurn, P.D. et al. T- and B-cell-deficient mice with experimental stroke have reduced lesion size and inflammation. J. Cereb. Blood Flow Metab. 27, 1798–1805 (2007).

    CAS  Article  Google Scholar 

  37. 37

    Schroeter, M. & Jander, S. T-cell cytokines in injury-induced neural damage and repair. Neuromolecular Med. 7, 183–195 (2005).

    CAS  Article  Google Scholar 

  38. 38

    Wajant, H., Pfizenmaier, K. & Scheurich, P. Tumor necrosis factor signaling. Cell Death Differ. 10, 45–65 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Baird, A.E. The forgotten lymphocyte: immunity and stroke. Circulation 113, 2035–2036 (2006).

    Article  Google Scholar 

  40. 40

    Campanella, M., Sciorati, C., Tarozzo, G. & Beltramo, M. Flow cytometric analysis of inflammatory cells in ischemic rat brain. Stroke 33, 586–592 (2002).

    Article  Google Scholar 

  41. 41

    Fisson, S. et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 198, 737–746 (2003).

    CAS  Article  Google Scholar 

  42. 42

    Frenkel, D. et al. Neuroprotection by IL-10–producing MOG CD4+ T cells following ischemic stroke. J. Neurol. Sci. 233, 125–132 (2005).

    CAS  Article  Google Scholar 

  43. 43

    Strle, K. et al. Interleukin-10 in the brain. Crit. Rev. Immunol. 21, 427–449 (2001).

    CAS  Article  Google Scholar 

  44. 44

    Vignali, D.A., Collison, L.W. & Workman, C.J. How regulatory T cells work. Nat. Rev. Immunol. 8, 523–532 (2008).

    CAS  Article  Google Scholar 

  45. 45

    O'Garra, A., Vieira, P.L., Vieira, P. & Goldfeld, A.E. IL-10–producing and naturally occurring CD4+ Tregs: limiting collateral damage. J. Clin. Invest. 114, 1372–1378 (2004).

    CAS  Article  Google Scholar 

  46. 46

    Vogel, J., Mobius, C. & Kuschinsky, W. Early delineation of ischemic tissue in rat brain cryosections by high-contrast staining. Stroke 30, 1134–1141 (1999).

    CAS  Article  Google Scholar 

  47. 47

    Schallert, T., Hernandez, T.D. & Barth, T.M. Recovery of function after brain damage: severe and chronic disruption by diazepam. Brain Res. 379, 104–111 (1986).

    CAS  Article  Google Scholar 

  48. 48

    Steiner, G.E., Ecker, R.C., Kramer, G., Stockenhuber, F. & Marberger, M.J. Automated data acquisition by confocal laser scanning microscopy and image analysis of triple stained immunofluorescent leukocytes in tissue. J. Immunol. Methods 237, 39–50 (2000).

    CAS  Article  Google Scholar 

  49. 49

    Blais, V. & Rivest, S. Effects of TNF-α and IFN-γ on nitric oxide–induced neurotoxicity in the mouse brain. J. Immunol. 172, 7043–7052 (2004).

    CAS  Article  Google Scholar 

  50. 50

    Nadeau, S. & Rivest, S. Role of microglial-derived tumor necrosis factor in mediating CD14 transcription and nuclear factor κ B activity in the brain during endotoxemia. J. Neurosci. 20, 3456–3468 (2000).

    CAS  Article  Google Scholar 

Download references


This study was supported by grants from the Else-Kröner Fresenius Stiftung and the Ministerium für Wissenschaft und Kultur Baden-Württemberg to R.V. We would like to thank H. Bürgers and D. Stefan for excellent technical assistance and I. Galani (German Cancer Research Center, Heidelberg) for providing the Rag2−/− mice.

Author information




A.L. designed and performed experiments, analyzed data and wrote the manuscript; H.D. performed experiments and analyzed data; E.S.-P. provided crucial input on Treg cell function and contributed to experimental design and manuscript writing; C.V. designed experiments and contributed to manuscript writing; C.S. designed experiments and analyzed data; S.R. performed experiments and analyzed data; T.G. provided specific input to flow cytometric analysis and contributed to manuscript writing; R.V. initiated and directed the entire study, designed experiments, analyzed data and wrote the manuscript.

Corresponding author

Correspondence to Roland Veltkamp.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1—4 and Supplementary Methods (PDF 1037 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Liesz, A., Suri-Payer, E., Veltkamp, C. et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15, 192–199 (2009).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing