Regulatory T Lymphocytes Help Limit Stroke Damage to the Brain

Regulatory T lymphocytes (Treg) limit the extent of secondary damage following stroke by blocking the production of neurotoxins and modulating the action of lymphocytes and microglia in the brain, according to a new study.

Researchers at the University Laval (Quebec, Canada) and the University Heidelberg (Germany) examined the role of the key immunomodulators cluster of differentiation 4 (CD4), CD25, forkhead box P3 (Foxp3), and regulatory T lymphocytes Treg cells following experimental brain ischemia in mice. The researchers found that depletion of Treg cells profoundly increased delayed brain damage and deteriorated functional outcome; additionally, an absence of Treg cells augmented post-ischemic activation of resident and invading inflammatory cells including microglia and T cells, the main sources of harmful cerebral tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), respectively. The researchers also found that intracerebral interleukin-10 (IL10) substitution abrogated the cytokine overexpression after Treg cell depletion and prevented secondary infarct growth, whereas transfer of IL10-deficient Treg cells in an adoptive transfer model was ineffective. The researchers therefore concluded that Treg cells are major cerebroprotective modulators of inflammatory brain damage following a stroke by targeting multiple inflammatory pathways, and the IL-10 signaling process was found to be essential for the immunomodulatory effect the Treg cells mediated. The study was published on January 25, 2009, in the online version of Nature Medicine.

"These results lead us to believe that we could better preserve crucial functions like sight, speech, or control of the limbs if we rapidly stimulated the production of Treg cells in stroke victims,” said lead author Professor Serge Rivest, Ph.D., of the laboratory of molecular endocrinology at Laval. "We also believe that the protective effect of Treg cells could be used to treat other types of brain damage, especially that caused by head injury.”

Regulatory T cells are a specialized subpopulation of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. Treg cells are produced in the bone marrow and other organs of the immune system, and they migrate to the brain during the first few days after a stroke; experiments have shown that three days after a stroke, the affected area of the brain is 20% larger in mice without regulatory T (Treg) cells than in normal mice. Interest in Treg cells has been heightened by evidence from other experimental mouse models demonstrating that the immunosuppressive potential of these cells can be harnessed therapeutically to treat autoimmune diseases, facilitate transplantation tolerance, or potentate cancer immunotherapy.

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University Laval
University Heidelberg