ADAM17-Mediated Processing of TNF- alpha Expressed by Antiviral Effector CD8+ T Cells Is Required for Severe T-Cell-Mediated Lung Injury: e79340

• Published in: PloS one 2013-11, Vol.8 (11)
• Main Authors: DeBerge, Matthew P, Ely, Kenneth H, Cheng, Guang-Shing, Enelow, Richard I
• Format: Article
• Language: English
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0079340

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- alpha is required for severe and lethal lung injury following recognition of an influenza antigen expressed by alveolar epithelial cells. Since TNF- alpha 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- alpha processing in CD8+ T-cell-mediated injury. In this study we observed that inhibition of ADAM17-mediated processing of TNF- alpha 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- alpha 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- alpha 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.