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 (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.

The neuron-astrocyte-microglia triad in CA3 after chronic cerebral hypoperfusion in the rat: Protective effect of dipyridamole

“…It was also found that CA1 pyramidal cell death, 1 day after OGD, was significantly increased in microglia-depleted organotypic cultures, again suggesting a neuroprotective role of the normal content of microglia (Montero et al 2009). Since it is well known that the CA3 area of the hippocampus is more resistant than the CA1 to ischemic insults, the increase of microglia cells that occurs in concert with the removal of dead cells (Nathan and Ding 2010) may have both anti-inflammatory effects and consequently neuroprotective properties (Liesz et al 2009). Indeed, the microglia increase in CA3 and decrease in CA1 (Lana et al 2014) may explain the higher sensitivity of CA1 pyramidal cells to an ischemic insult.…”

Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits

“…However, IL-10 is expressed as an anti-inflammatory cytokine that is produced from regulatory T lymphocytes (Treg). It was reported that IL-10 could suppress the neurotoxic functions of TNF-α and IFN-γ [21] and alleviate BBB damage. IL-10 is also conductive to the restoration of nerve cells and has a neuroprotective effect [22] .…”

Clinical Trials of Immunomodulation in Ischemic Stroke

“…A substantial role for the adaptive immune response after stroke is increasingly recognized. Transgenic animals deficient in lymphocytes consistently have smaller infarcts in different stroke models [23][24][25][26]. Moreover, antibody-mediated depletion of CD4 + , CD8 + , and γδ T cells reduced infarct volume and improved functional outcome [25,[27][28][29].…”