Journal Article

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

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

2013

Overview

Influenza infection in humans evokes a potent CD8.sup.+ 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.sup.+ 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.sup.+ T-cell-mediated injury. In this study we observed that inhibition of ADAM17-mediated processing of TNF-[alpha] by CD8.sup.+ 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.sup.+ 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.sup.+ 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.

• Publisher: Public Library of Science
• Subject: Antigens / Antiviral agents / Genetic engineering / Health aspects / Influenza / Lung diseases / T cells / Tumor necrosis factor