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Requirement for Tumor Necrosis Factor-Receptor 2 in Alveolar Chemokine Expression Depends upon the Form of the Ligand

Department of Medicine, Yale University School of Medicine, New Haven, Connecticut; Departments of Surgery and Pathology, University of Virginia School of Medicine, Charlottesville, Virginia; and Department of Molecular Biomedical Research, VIB, Ghent University, Ghent, Belgium

Correspondence and requests for reprints should be addressed to Richard I. Enelow, VA Connecticut Healthcare System/111A, 950 Campbell Ave., West Haven, CT 06516. E-mail: richard.enelow{at}yale.edu

Respiratory virus infection evokes a potent T-cell response that 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 that is critically dependent upon tumor necrosis factor (TNF)- expressed by the CD8+ T cells and is largely dependent upon TNF-receptor 1 expression on the alveolar epithelial target cells. TNF-receptor 2 (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 monocyte chemoattractant protein (MCP)-1 expression specifically in response to soluble TNF-, suggesting an important role for this receptor in bystander lung injury. However, TNF-R2 was dispensable 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 seem to be additive. Because 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.

Key Words: chemokines • inflammation • lung • T cells

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