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.
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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.
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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). https://doi.org/10.1038/nm.1927
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