Proteolytic processing of TNF-α by influenza-specific CD8+ T cells is required for alveolar epithelial cell MIP-2 production and severe lung injury in a transgenic mouse model of influenza infection (67.3)

Abstract

Abstract Adoptive transfer of influenza hemagglutinin (HA)-specific CD8+ T cells into transgenic mice expressing influenza HA on the alveolar epithelium results in epithelial cell production of monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-2, the subsequent mononuclear cell infiltration and diffuse alveolar damage. The lung injury observed in this model is mediated by CD8+ T cell production of tumor necrosis factor (TNF)-α. TNF-α is expressed as a transmembrane (tm) protein that is proteolytically processed 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 HA-specific CD8+ T cells that only express a noncleavable tmTNF-α (TM). We found that proteolytic processing of tmTNF-α to sTNF-α was required for alveolar epithelial cell production of MIP-2 but not MCP-1 in vitro. Furthermore, this epithelial cell production of MIP-2 required ERK activation that was dependent on TNF-α signaling through TNF-α receptor II. Finally, we adoptively transferred HA-specific TM CD8+ T cells into HA transgenic mice and found that TM CD8+ T cells failed to induce alveolar epithelial cell MIP-2 production and neutrophil infiltration, and produced milder lung injury than transferred wild-type CD8+ T cells. Taken together, these findings suggest that proteolytic processing of tmTNF-α to sTNF-α is a critical event regulating CD8+ T cell mediated injury in a transgenic mouse model of influenza infection.