Pulmonary immunopathology mediated by proteolytic processing of TNF-α by antiviral CD8+ T cells (105.11)

Abstract

Abstract Infection with influenza virus evokes a potent CD8+ T cell response that may contribute to lung immunopathology. Recognition of alveolar anitgen by CD8+ T cells results in significant injury that is critically dependent on TNF-α expressed by CD8+ T cells and is largely mediated by the secretion of chemokines by alveolar epithelial cells and the subsequent pulmonary infiltration. TNF-α is expressed as a transmembrane (tm) protein that is proteolytically processed by TNF-α converting enzyme (TACE) to produce soluble (s) TNF-α. To determine the roles of tmTNF-α and sTNF-α in CD8+ T cell mediated lung injury, we generated CD8+ T cells that express either a noncleavable tmTNF-α or have a deletion in the catalytic domain of TACE. Both T cells are impaired in sTNF-α production but exhibited no defect in other effector functions. In vitro analysis indicated that proteolytic processing of tmTNF-α to sTNF-α was required to induce alveolar epithelial cell expression of macrophage inflammatory protein-2. Furthermore, inhibition of proteolytic processing of TNF-α resulted in reduced induction of alveolar epithelial cell chemokines, less neutrophil infiltration and milder lung injury, though these T cells exhibited no defect in antiviral activity in vivo. This indicates that proteolytic processing of tmTNF-α to sTNF-α is a critical event in the initiation of CD8+ T cell mediated lung injury and represents a potential mechanism of regulation of immunopathology during an influenza infection.