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C D8⁺ T lymphocyte responses are a critical arm of the immune response to respiratory virus infection and may play a role in the pathogenesis of interstitial lung disease. We have shown that CD8⁺ T cells induce significant lung injury in the absence of virus infection by adoptive transfer into mice with alveolar expression of a viral transgene. The injury is characterized by the parenchymal infiltration of host cells, primarily macrophages, which correlates with physiologic deficits in transgenic animals. CD8⁺ T cell–mediated lung injury can occur in the absence of perforin and Fas expression as long as TNF-α is available. Here, we show that the effect of TNF-α expressed by CD8⁺ T cells is mediated not exclusively by cytotoxicity, but also through the activation of alveolar target cells and their expression of inflammatory mediators. CD8⁺ T cell recognition of alveolar cells in vitro triggered monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) expression in the targets, which was mediated by TNF-α. Antigen-dependent alveolar MCP-1 expression was observed in vivo as early as 3 hours after CD8⁺ T cell transfer and depended upon TNF-R1 expression in transgenic recipients. MCP-1 neutralization significantly reduced parenchymal infiltration after T cell transfer. We conclude that alveolar epithelial cells actively participate in the inflammation and lung injury associated with CD8⁺ T cell recognition of alveolar antigens.This article may have been published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. J. Clin. Invest. 106:R49–R58 (2000).