Perforin-independent CD8+ T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-α -: Relative insensitivity to Fas ligand

被引:79
作者
Liu, AN
Mohammed, AZ
Rice, WR
Fiedeldey, DT
Liebermann, JS
Whitsett, JA
Braciale, TJ
Enelow, RI
机构
[1] Univ Virginia, Sch Med, Berine B Carter Ctr Immunol Res, Charlottesville, VA 22908 USA
[2] Univ Virginia, Sch Med, Dept Med, Charlottesville, VA 22908 USA
[3] Univ Virginia, Sch Med, Dept Pathol, Charlottesville, VA 22908 USA
[4] Univ Virginia, Sch Med, Dept Microbiol, Charlottesville, VA 22908 USA
[5] Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA
关键词
D O I
10.1165/ajrcmb.20.5.3585
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:849 / 858
页数:10
相关论文
共 77 条
[31]  
Graham Mary Beth, 1996, Methods (Orlando), V9, P439, DOI 10.1006/meth.1996.0050
[32]   Apoptosis and expression of Fas/Fas ligand mRNA in bleomycin-induced pulmonary fibrosis in mice [J].
Hagimoto, N ;
Kuwano, K ;
Nomoto, Y ;
Kunitake, R ;
Hara, N .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1997, 16 (01) :91-101
[33]   Induction of apoptosis and pulmonary fibrosis in mice in response to ligation of fas antigen [J].
Hagimoto, N ;
Kuwano, K ;
Miyazaki, H ;
Kunitake, R ;
Fujita, M ;
Kawasaki, M ;
Kaneko, Y ;
Hara, N .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1997, 17 (03) :272-278
[34]   Pulmonary mechanical and immunologic dysfunction in a murine model of AIDS [J].
Hartsfield, CL ;
Lipke, D ;
Lai, YL ;
Cohen, DA ;
Gillespie, MN .
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 1997, 272 (04) :L699-L706
[35]   Fas system and apoptosis in viral hepatitis [J].
Hayashi, N ;
Mita, E .
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, 1997, 12 (9-10) :S223-S226
[36]  
HENKART P, 1993, CYTOTOXIC CELLS, P9
[37]   LYMPHOCYTE-MEDIATED CYTOTOXICITY - 2 PATHWAYS AND MULTIPLE EFFECTOR MOLECULES [J].
HENKART, PA .
IMMUNITY, 1994, 1 (05) :343-346
[38]   Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice [J].
Itoh, N ;
Imagawa, A ;
Hanafusa, T ;
Waguri, M ;
Yamamoto, K ;
Iwahashi, H ;
Moriwaki, M ;
Nakajima, H ;
Miyagawa, J ;
Namba, M ;
Makino, S ;
Nagata, S ;
Kono, N ;
Matsuzawa, Y .
JOURNAL OF EXPERIMENTAL MEDICINE, 1997, 186 (04) :613-618
[39]   FAS AND PERFORIN PATHWAYS AS MAJOR MECHANISMS OF T-CELL-MEDIATED CYTOTOXICITY [J].
KAGI, D ;
VIGNAUX, F ;
LEDERMANN, B ;
BURKI, K ;
DEPRAETERE, V ;
NAGATA, S ;
HENGARTNER, H ;
GOLSTEIN, P .
SCIENCE, 1994, 265 (5171) :528-530
[40]  
Katzenstein AL., 1997, KATZENSTEIN ASKINS S