and specific aims): 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 cytologic activity (utilizing at least two distinct molecular mechanisms) 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 goal of this project 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.
The specific aims are: 1) Characterization of the pattern of lung injury and the pathophysiologic consequences of alveolar injury produced by CD8+T cells, in a series of in vivo adoptive transfer experiments. T cell-mediated injury will be characterized both in terms of structural, as well as physiologic, abnormalities of the lung. 2) The development of an in vitro system for analysis of specific interactions between T lymphocytes and alveolar epithelial cells in order to probe the antigen processing capabilities of alveolar epithelial cells, and the molecular mechanisms involved in CD8+T cell cytotoxic injury to epithelial cells. 3) An analysis of the mechanisms by which CD8+T cells directly induce lung injury in vivo, with a series of adoptive transfer experiments utilizing genetically deficient T cells and recipient mice.
