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Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke

Abstract

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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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.

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Acknowledgements

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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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.

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Correspondence to Roland Veltkamp.

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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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