| First Author | DeBerge MP | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 11 | Pages | e79340 |
| PubMed ID | 24223177 | Mgi Jnum | J:209328 |
| Mgi Id | MGI:5566966 | Doi | 10.1371/journal.pone.0079340 |
| Citation | DeBerge MP, et al. (2013) ADAM17-mediated processing of TNF-alpha expressed by antiviral effector CD8+ T cells is required for severe T-cell-mediated lung injury. PLoS One 8(11):e79340 |
| abstractText | 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. |
