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2013 ; 8
(11
): e79340
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gab.com Text
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ADAM17-mediated processing of TNF-? expressed by antiviral effector CD8+ T cells
is required for severe T-cell-mediated lung injury
#MMPMID24223177
DeBerge MP
; Ely KH
; Cheng GS
; Enelow RI
PLoS One
2013[]; 8
(11
): e79340
PMID24223177
show ga
Influenza infection in humans evokes a potent CD8(+) T-cell response, which is
important for clearance of the virus but may also exacerbate pulmonary pathology.
We have previously shown in mice that CD8(+) T-cell expression of TNF-? is
required for severe and lethal lung injury following recognition of an influenza
antigen expressed by alveolar epithelial cells. Since TNF-? is first expressed as
a transmembrane protein that is then proteolytically processed to release a
soluble form, we sought to characterize the role of TNF-? processing in CD8(+)
T-cell-mediated injury. In this study we observed that inhibition of
ADAM17-mediated processing of TNF-? by CD8(+) T cells significantly attenuated
the diffuse alveolar damage that occurs after T-cell transfer, resulting in
enhanced survival. This was due in part to diminished chemokine expression, as
TNF-? processing was required for lung epithelial cell expression of CXCL2 and
the subsequent inflammatory infiltration. We confirmed the importance of CXCL2
expression in acute lung injury by transferring influenza-specific CD8(+) T cells
into transgenic mice lacking CXCR2. These mice exhibited reduced airway
infiltration, attenuated lung injury, and enhanced survival. Theses studies
describe a critical role for TNF-? processing by CD8(+) T cells in the initiation
and severity of acute lung injury, which may have important implications for
limiting immunopathology during influenza infection and other human infectious or
inflammatory diseases.