Article ; Online: ADAM17-mediated processing of TNF-α expressed by antiviral effector CD8+ T cells is required for severe T-cell-mediated lung injury.
2013 Volume 8, Issue 11, Page(s) e79340
Abstract: ... that CD8(+) T-cell expression of TNF-α is required for severe and lethal lung injury following recognition ... of ADAM17-mediated processing of TNF-α by CD8(+) T cells significantly attenuated the diffuse alveolar ... the role of TNF-α processing in CD8(+) T-cell-mediated injury. In this study we observed that inhibition ...
| Abstract | 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-α is required for severe and lethal lung injury following recognition of an influenza antigen expressed by alveolar epithelial cells. Since TNF-α 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-α processing in CD8(+) T-cell-mediated injury. In this study we observed that inhibition of ADAM17-mediated processing of TNF-α 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-α 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-α 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. |
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| MeSH term(s) | ADAM Proteins/deficiency ; ADAM Proteins/metabolism ; ADAM17 Protein ; Animals ; CD8-Positive T-Lymphocytes/immunology ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Female ; Gene Expression Regulation ; Humans ; Lung/immunology ; Lung/metabolism ; Lung/pathology ; Lung/virology ; Lung Injury/immunology ; Lung Injury/metabolism ; Lung Injury/pathology ; Lung Injury/virology ; Macrophages/immunology ; Mice ; Neutrophil Infiltration ; Proteolysis ; Receptors, Interleukin-8B/metabolism ; Signal Transduction ; Solubility ; Tumor Necrosis Factor-alpha/chemistry ; Tumor Necrosis Factor-alpha/metabolism |
| Chemical Substances | Receptors, Interleukin-8B ; Tumor Necrosis Factor-alpha ; ADAM Proteins (EC 3.4.24.-) ; ADAM17 Protein (EC 3.4.24.86) ; ADAM17 protein, human (EC 3.4.24.86) ; Adam17 protein, mouse (EC 3.4.24.86) |
| Language | English |
| Publishing date | 2013-11-06 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 2267670-3 |
| ISSN | 1932-6203 ; 1932-6203 |
| ISSN (online) | 1932-6203 |
| ISSN | 1932-6203 |
| DOI | 10.1371/journal.pone.0079340 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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