Perforin-independent CD8+ T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-α -: Relative insensitivity to Fas ligand
Perforin-independent CD8+ T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-α -: Relative insensitivity to Fas ligand
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DOI：
10.1165/ajrcmb.20.5.3585
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发表时间：
1999-05-01
影响因子：
6.4
通讯作者：
Enelow, RI
中科院分区：
文献类型：
--
作者：
Liu, AN;Mohammed, AZ;Enelow, RI
CD 8（+）T细胞在许多炎症性肺部疾病中发挥重要的病理生理作用。该T细胞亚群的主要效应子功能是病毒感染细胞的细胞溶解，并且广泛认为存在两种主要的分子机制：穿孔素/颗粒酶介导的细胞溶解途径和诱导靶细胞凋亡的Fas配体（FasL）-Fas（CD 95/APO-1）途径。这一结论主要基于造血细胞系作为靶细胞获得的数据。还有越来越多的证据表明，Fas参与各种炎症性疾病状态中凋亡信号的转导，特别是涉及肝脏和肺。在本研究中，我们利用一种新的体外试验直接评估CD 8（+）T细胞介导的肺泡上皮细胞溶解中的效应机制。我们目前的证据表明，快速诱导，Fas介导的凋亡并不直接有助于T细胞介导的肺泡上皮细胞的细胞溶解，即使Fas的表达和功能对这些细胞。我们还证明了CD 8（+）T细胞对肺泡上皮细胞的非穿孔素依赖性细胞溶解活性完全由CD 8（+）T细胞上表达的肿瘤坏死因子-α（TNF-α）解释。此外，我们还发现，抗病毒CD 8（+）T细胞对肺泡上皮细胞的旁观者细胞溶解是完全不依赖穿孔素的。这种活性仅由TNF-α介导。肺泡上皮衍生的细胞和原代小鼠II型细胞都显示出对可溶性TNF-α引发的凋亡的易感性，而不需要转录或翻译抑制。我们还通过将穿孔素缺陷型抗病毒CD 8（+）T细胞过继转移到在II型上皮细胞中表达靶抗原的转基因小鼠中，证实了肺泡II型细胞对Fast的体内抗性。无论这些动物是否表达Fas，转基因CD 8（+）T细胞受体均发生显著的肺损伤。此外，用TNF-α抗体预孵育T细胞完全消除了损伤。这些结果表明，肺泡上皮细胞对T细胞触发的、TNF-α介导的凋亡相对敏感，并且对Fast触发的凋亡具有抗性。这些观察结果可能对理解间质性和炎症性肺病的病理生理学有重要的影响。
CD8(+) T cells appear to play an important pathophysiologic role in many inflammatory lung diseases. The primary effector function of this T-cell subset is cytolysis of virus-infected cells, and it is widely believed that there are two primary molecular mechanisms by which this occurs: the perforin/granzyme-mediated pathway of cytolysis, and the Fas ligand (FasL)-Fas (CD95/APO-1) pathway of induction of target-cell apoptosis. This conclusion is based primarily on data obtained with hematopoetic cell lines as target cells. There is also a growing body of evidence that Fas is involved in the transduction of apoptotic signals in a variety of inflammatory disease states, particularly involving the liver and the lung. In the study reported here we took advantage of a novel in vitro assay to directly assess the effector mechanisms employed in CD8(+) T-cell-mediated cytolysis of alveolar epithelial cells. We present evidence that Fast-induced, Fas-mediated apoptosis does not directly contribute to T-cell-mediated cytolysis of alveolar epithelial-derived cells, even though Fas is expressed and functional on these cells. We also demonstrated that the perforin-independent cytolytic activity of CD8(+) T cells against alveolar epithelial-derived cells is explained entirely by tumor necrosis factor-alpha (TNF-alpha), which is expressed on CD8(+) T cells. Furthermore, we show that bystander cytolysis of alveolar epithelial-derived cells by antiviral CD8(+) T cells is entirely perforin-independent. This activity is mediated exclusively by TNF-alpha. Both alveolar epithelial-derived cells and primary murine type II cells show susceptibility to apoptosis triggered by soluble TNF-alpha, without the need for transcriptional or translational inhibition. We also confirmed the resistance of alveolar type II cells to Fast in vivo by performing adoptive transfer of perforin-deficient antiviral CD8(+) T cells into transgenic mice expressing a target antigen in type Il epithelial cells. Significant lung injury developed in the transgenic CD8(+) T-cell recipients, whether or not Fas was expressed in these animals. Furthermore, preincubation of the T cells with antibody to TNF-alpha completely abolished the injury. These results suggest that alveolar epithelial cells are relatively sensitive to T cell-triggered, TNF-alpha-mediated apoptosis, and resistant to apoptosis triggered by Fast. These observations may have important ramifications for understanding of the pathophysiology of interstitial and inflammatory lung diseases.