Respiratory virus infection evokes a potent T cell response which may result in a considerable insult to the structural and functional integrity of the gas exchange units of the lung. Alveolar antigen recognition by CD8+ T lymphocytes results in significant injury which is critically dependent upon TNF- expressed by the CD8+ T cells, and largely dependent upon TNF-receptor 1 (TNF-R1) expression on the alveolar epithelial target cells. TNF-R2-deficient mice were used to demonstrate that CD8+ T cell-mediated lung injury associated with clearance of experimental influenza requires TNF-R2 for full expression of immunopathology. In vitro analysis indicates that alveolar cell expression of TNF-R2 is critical in the induction of epithelial MCP-1 expression specifically in response to soluble TNF-, suggesting an important role for this receptor in bystander lung injury. However, TNF-R2 was entirely dispensible for induction of alveolar MCP-1 expression in response to transmembrane TNF- expressed by antigen-specific CD8+ T cells, and the effects of the two receptors appear additive. Since TNF-R2 may be rapidly shed as part of feedback inhibition of bystander inflammation, this suggests a mechanism by which immunopathology in respiratory virus infection may be regulated, and by which T cell-receptor-dependent TNF- activity might bypass such negative regulation, for contact-dependent antiviral activities.