An. Liu et al., Perforin-independent CD8(+) T-cell-mediated cytotoxicity of alveolar epithelial cells is preferentially mediated by tumor necrosis factor-alpha - Relative insensitivity to Fas ligand, AM J RESP C, 20(5), 1999, pp. 849-858
Citations number
76
Categorie Soggetti
da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
CD8(+) T cells appear to play an important pathophysiologic role in many in
flammatory lung diseases. The primary effector function of this T-cell subs
et is cytolysis of virus-infected cells, and it is widely believed that the
re 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 b
ased primarily on data obtained with hematopoetic cell lines as target cell
s. There is also a growing body of evidence that Fas is involved in the tra
nsduction 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 epithe
lial cells. We present evidence that Fast-induced, Fas-mediated apoptosis d
oes not directly contribute to T-cell-mediated cytolysis of alveolar epithe
lial-derived cells, even though Fas is expressed and functional on these ce
lls. We also demonstrated that the perforin-independent cytolytic activity
of CD8(+) T cells against alveolar epithelial-derived cells is explained en
tirely by tumor necrosis factor-alpha (TNF-alpha), which is expressed on CD
8(+) T cells. Furthermore, we show that bystander cytolysis of alveolar epi
thelial-derived cells by antiviral CD8(+) T cells is entirely perforin-inde
pendent. This activity is mediated exclusively by TNF-alpha. Both alveolar
epithelial-derived cells and primary murine type II cells show susceptibili
ty to apoptosis triggered by soluble TNF-alpha, without the need for transc
riptional or translational inhibition. We also confirmed the resistance of
alveolar type II cells to Fast in vivo by performing adoptive transfer of p
erforin-deficient antiviral CD8(+) T cells into transgenic mice expressing
a target antigen in type Il epithelial cells. Significant lung injury devel
oped in the transgenic CD8(+) T-cell recipients, whether or not Fas was exp
ressed in these animals. Furthermore, preincubation of the T cells with ant
ibody to TNF-alpha completely abolished the injury. These results suggest t
hat 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.