T lymphocytes infiltrate the lung in a variety of human lung diseases which are characterized by acute and chronic lung injury. The mechanisms underlying the induction of injury to the lung, and the resultant impact on pulmonary physiology remain obscure. T cells are capable of expressing a variety of effector functions, including direct cytolytic activity as well as the secretion of a number of soluble mediators of inflammation. It is likely that T cell infiltration of the lung results in damage to parenchymal cells by several direct and indirect mechanisms.
The aim of this proposal is to understand the specific mechanisms by which T cells directly injure the lung, particularly the alveolar epithelial cell. The impact of this injury on respiratory physiology will also be analyzed. A transgenic murine model has been developed for this purpose, in which T cells directed to a model target antigen are activated in vitro, and adoptively transferred into a transgenic recipient which expresses that target antigen in the lung. Severe interstitial pneumonitis is generated by the adoptive transfer of activated CD8+ T cells, resulting in significant lung injury and death within one week. It appears that TNF-alpha expressed by CD8+ T cells is an important contributor to T cell-mediated lung injury. It also appears that specific T cell recognition of antigen on alveolar epithelial cells triggers active transcription in the target cell and expression of inflammatory chemokines, which are a primary determinant of the severity of injury. To investigate the specific mechanisms by which CD8+ T cell recognition induces alveolar injury, as well as the physiologic consequences of injury, the following specific aims will be addressed: 1) to characterize the impact of TNF-alpha neutralization of lung injury initiated by CD8+ T cell transfer; 2) to analyze specific interactions between CD8+ T lymphocyte and alveolar epithelial cells in vitro; and 3) to analyze the mechanisms of TNF-dependent CD8+ T cell-mediated injury in vivo.
