Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke
Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke
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DOI：
10.1038/nm.1927
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发表时间：
2009-02-01
期刊：
影响因子：
82.9
通讯作者：
Veltkamp, Roland
中科院分区：
文献类型：
--
作者：
Liesz, Arthur;Suri-Payer, Elisabeth;Veltkamp, Roland
全身和局部炎症过程在缺血性卒中的病理生理学中具有关键的、主要是有害的作用。目前，对内源性免疫反调节机制知之甚少。我们检测了实验性脑缺血后关键免疫调节因子CD 4（+）CD 25（+）叉头盒P3（Foxp 3）（+）调节性T淋巴细胞（T-reg细胞）的作用。耗尽的T-reg细胞大大增加迟发性脑损伤和恶化的功能结果。缺乏T-reg细胞增强了缺血后驻留和侵入炎性细胞的激活，包括小胶质细胞和T细胞，分别是有害的脑肿瘤坏死因子-α（TNF-α）和干扰素-γ（IFN-γ）的主要来源。在T-reg细胞耗竭的小鼠中，TNF-α的早期活化和IFN-γ的延迟中和防止了梗死生长。脑内白细胞介素-10（IL-10）替代废除了T-reg细胞耗竭后的细胞因子过表达，并防止继发性梗死生长，而在过继转移模型中转移IL-10缺陷型T-reg细胞是无效的。总之，T-reg细胞是针对多种炎症途径的缺血后炎症性脑损伤的主要神经保护性调节剂。IL-10信号传导对其免疫调节作用至关重要。
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.