ADAM17-mediated processing of TNF-α expressed by antiviral effector CD8+ T cells is required for severe T-cell-mediated lung injury

Matthew DeBerge, Kenneth H. Ely, Guang Shing Cheng, Richard I. Enelow

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere79340
JournalPloS one
Volume8
Issue number11
DOIs
StatePublished - Nov 6 2013

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T-cells
Lung Injury
Antiviral Agents
T-lymphocytes
lungs
T-Lymphocytes
influenza
Human Influenza
Processing
Acute Lung Injury
Infiltration
mice
epithelial cells
immunopathology
Alveolar Epithelial Cells
Lung
transmembrane proteins
Survival
Pathology
chemokines

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

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title = "ADAM17-mediated processing of TNF-α expressed by antiviral effector CD8+ T cells is required for severe T-cell-mediated lung injury",
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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ADAM17-mediated processing of TNF-α expressed by antiviral effector CD8+ T cells is required for severe T-cell-mediated lung injury. / DeBerge, Matthew; Ely, Kenneth H.; Cheng, Guang Shing; Enelow, Richard I.

In: PloS one, Vol. 8, No. 11, e79340, 06.11.2013.

Research output: Contribution to journalArticle

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