Antigen Dependently Activated Cluster of Differentiation 8-Positive T Cells Cause Perforin-Mediated Neurotoxicity in Experimental Stroke
Antigen Dependently Activated Cluster of Differentiation 8-Positive T Cells Cause Perforin-Mediated Neurotoxicity in Experimental Stroke
复制标题
DOI：
10.1523/jneurosci.1867-14.2014
复制
发表时间：
2014-12-10
影响因子：
5.3
通讯作者：
Veltkamp, Roland
中科院分区：
文献类型：
--
作者：
Mracsko, Eva;Liesz, Arthur;Veltkamp, Roland
神经炎症在卒中后继发性脑损伤中起关键作用。虽然促炎细胞因子的有害作用已被很好地描述，但入侵免疫细胞对缺血脑的直接细胞毒作用及其抗原依赖激活的重要性基本上是未知的。在这里，我们研究了适应性和先天免疫细胞-细胞毒性T淋巴细胞(CTL)和自然杀伤(NK)细胞-共享直接穿孔素介导的细胞毒途径对小鼠脑缺血后预后的影响。虽然CTL和NK细胞都侵入了缺血脑，但只有脑浸润性CTL而不是NK细胞比他们的脾对应物更活跃。在两种缺血模型中，去除CTL可减少脑梗塞体积和行为缺陷，而去除NK细胞则没有影响。相应地，过继CTL从野生型转移到Rag1基因敲除小鼠增加了梗塞面积。从穿孔素基因敲除小鼠或干扰素-γ基因敲除小鼠向Rag1基因敲除小鼠过继转移CTL表明，CTL神经毒性是由穿孔素介导的。因此，从野生型或干扰素-γ基因敲除小鼠中分离出的CTL，而不是从穿孔素基因敲除小鼠中分离出来的CTL，在体外可以诱导神经细胞死亡。与野生型CTL相比，来自卵清蛋白特异性T细胞受体转基因小鼠的CTL没有被激活，而且渗透到缺血脑中的比例更低。它们的转移不会增加Rag1基因敲除小鼠的梗塞面积，这表明抗原依赖的激活是CTL神经毒性的重要组成部分。我们的发现强调了抗原依赖的、直接的细胞毒免疫反应在卒中中的重要性，并建议调节CTL及其效应通路作为卒中治疗的潜在新策略。
Neuroinflammation plays a key role in secondary brain damage after stroke. Although deleterious effects of proinflammatory cytokines are well characterized, direct cytotoxic effects of invading immune cells on the ischemic brain and the importance of their antigen-dependent activation are essentially unknown. Here we examined the effects of adaptive and innate immune cells-cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells-that share the direct perforin-mediated cytotoxic pathway on outcome after cerebral ischemia in mice. Although CTLs and NK cells both invaded the ischemic brain, only brain-infiltrating CTLs but not NK cells were more activated than their splenic counterparts. Depletion of CTLs decreased infarct volumes and behavioral deficit in two ischemia models, whereas NK cell depletion had no effect. Correspondingly, adoptive CTL transfer from wild-type into Rag1 knock-out mice increased infarct size. Adoptive CTL transfer from perforin knock-out or interferon-gamma knock-out mice into Rag1 knock-out mice revealed that CTL neurotoxicity was mediated by perforin. Accordingly, CTLs isolated from wild-type or interferon-gamma knock-out but not from perforin knock-out mice induced neuronal cell death in vitro. CTLs derived from ovalbumin-specific T-cell receptor transgenic mice were not activated and infiltrated less into the ischemic brain compared with wild-type CTLs. Their transfer did not increase the infarct size of Rag1 knock-out mice, indicating antigen-dependent activation as an essential component of CTL neurotoxicity. Our findings underscore the importance of antigen-dependent, direct cytotoxic immune responses in stroke and suggest modulation of CTLs and their effector pathways as a potential new strategy for stroke therapy.