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 (T-reg cells), after experimental brain ischemia. Depletion of T-reg cells profoundly increased delayed brain damage and deteriorated functional outcome. Absence of T-reg cells augmented postischemic activation of resident and invading inflammatory cells including microglia and T cells, the main sources of deleterious cerebral tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), respectively. Early antagonization of TNF-alpha and delayed neutralization of IFN-gamma prevented infarct growth in T-reg cell-depleted mice. Intracerebral interleukin-10 (IL-10) substitution abrogated the cytokine overexpression after T-reg cell depletion and prevented secondary infarct growth, whereas transfer of IL-10 deficient T-reg cells in an adoptive transfer model was ineffective. In conclusion, T-reg cells are major cerebroprotective modulators of postischemic inflammatory brain damage targeting multiple inflammatory pathways. IL-10 signaling is essential for their immunomodulatory effect.