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Am. J. Respir. Cell Mol. Biol., Volume 20, Number 5, May, 1999 849-858

RAPID COMMUNICATION
Perforin-Independent CD8+ T-Cell-Mediated Cytotoxicity of Alveolar Epithelial Cells Is Preferentially Mediated by Tumor Necrosis Factor-alpha
Relative Insensitivity to Fas Ligand

Angela Ning Liu, Ashraf Z. Mohammed, Ward R. Rice, Dana T. Fiedeldey, Jennifer S. Liebermann, Jeffrey A. Whitsett, Thomas J. Braciale, and Richard I. Enelow

Beirne B. Carter Center for Immunology Research, and Departments of Medicine, Pathology and Microbiology, University of Virginia School of Medicine, Charlottesville, Virginia; and Children's Hospital Medical Center, Cincinnati, Ohio

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 FasL-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 FasL in vivo by performing adoptive transfer of perforin-deficient antiviral CD8+ T cells into transgenic mice expressing a target antigen in type II 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 FasL. These observations may have important ramifications for understanding of the pathophysiology of interstitial and inflammatory lung diseases.




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