Regulatory T Cells are Cerebroprotective in Acute Experimental Stroke

Regulatory T Cells Cerebroprotective Experimental Stroke
Regulatory T Cells – Experimental Stroke

A recent Nature Medicine study by Arthur Liesz et al. indicates that regulatory T cells (Treg) are cerebroprotective after experimental brain ischemia or stroke, and that interleukin (IL)-10 appears to be the major mediator of the cerebroprotective effects.

Recent evidence indicates that inflammatory mechanisms such as up-regulation of pro-inflammatory cytokines and leukocytes’ invasion in the brain contribute to the ischemic brain damage. Thus, the inflammatory response goes haywire after stroke, and the brain floods with immune mediators that can injure tissue and worsen outcome. In fact, inflammatory mechanisms that are activated within hours after brain ischemia represent a key target of current translational cerebrovascular research.

It is also known that the neuroendocrine-immune interactions contribute to a serious immune dysfunction after stroke, which includes severe systemic immunodepression related to life-threatening infections.

The regulatory T cells (Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells.

The thymus-derived CD4+CD25+Foxp3+ Treg cells play a key part in controlling immune responses by altering the activity of antigen-presenting cells via direct interaction and through secretion of anti-inflammatory cytokines, including IL-10 and transforming growth factor (TGF)-β.

Previous studies have reported that IL-10 has a beneficial effect in cerebral ischemia, that neuroprotective mucosal immunization is mediated by inducible regulatory lymphocytes and that Treg cells show relative resistance to cerebral ischemia.

The overall immune changes and the mechanisms of the immune dysfunction after brain ischemia or stroke remain poorly understood. This also includes the question of whether and how Treg are involved in cerebral ischemia.

In the Nature Medicine study, Arthur Liesz and colleagues from the Department of Neurology, University of Heidelberg, Heidelberg, Germany investigated the role Treg cells play after ischemic experimental stroke. The authors report that Treg prevent secondary infarct growth by counteracting excessive production of proinflammatory cytokines and by modulating invasion and/or activation of lymphocytes and microglia in the ischemic brain.

According to the authors – their major finding is that Treg cells prevent secondary infarct growth by counteracting excessive production of proinflammatory cytokines and by modulating invasion and/or activation of lymphocytes and microglia in the ischemic brain.

The German research group has found that Treg cells antagonize enhanced TNF-α and IFN-γ production, which induce delayed inflammatory brain damage, and that Treg cell–derived secretion of IL-10 is the key mediator of the cerebroprotective effect via suppression of proinflammatory cytokine production.

Of note, the endogenous protective effect of Treg cells was verified in two independent experimental paradigms, i.e., antibody-mediated depletion and adoptive cell transfer.

Importantly, proinflammatory cytokines, which are substantially upregulated in large infarcts, were elevated after circumscribed cortical ischemia only in Treg cell–depleted mice. TNF-a expression was elevated early after ischemia both in the brain, where it was predominantly generated by microglia and systemically in Treg cell–depleted mice. Further-more, early, but not delayed, i.c.v. antagonization effectively reduced the lesion size. These findings are in line with early involvement of TNF-α in the inflammatory cascade and its role in the induction of inflammatory pathways.

As per IL-10, which is a common signaling mechanism used by Treg cells. IL-10 potently reduced infarct size in normal mice and prevented delayed lesion growth after Treg cell depletion when injected i.c.v. This effect resulted from the suppression of overshooting proinflammatory cytokine expression in the absence of Treg cells.

The study is perhaps the first to examine the role of Treg cells in acute cerebral ischemia, and reveals a previously unrecognized role of Treg cells in mediating cerebral protection after stroke. Thus, it may provide new insights into the endogenous adaptive immune response after acute brain ischemia.

Source: Nat Med 2009, 15:192
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