This project proposes to investigate the role of monocyte and alveolar macrophage surface CD4 in inflammatory cell function in normal and diseased lungs. The basis of our proposed studies is predicated on the observations that the peripheral blood monocyte and the alveolar macrophage both express surface CD4, and that stimulation of these cells via CD4 using a novel CD4 binding lymphokine (Lymphocyte Chemoattractant Factor, LCF) recently cloned by Dr. Center's laboratory (Project 1) results in activation of signal transduction pathways and essential cell functions. Briefly summarized, LCF binding to monocyte CD4 results in rises in intracellular Ca++ and IP3 accompanied by enhanced migration and subsequent increases in cell surface expression of the MHC Class II antigen HLA-DR. With this as background, we will study selected aspects of mononuclear cell CD4 receptor function by determining the signals it transduces and the functions that result from its activation. There are several unique parts of our experiments. The first is the study of CD4 on two related cell types from the same individuals permitting us to ask questions about the process by which these cells adhere to endothelium, migrate into lung, the events of the maturation process as the monocyte converts to macrophage in vivo and in vitro. Second, we will be able to study the causes behind CD4 appearance and disappearance on the AM in vitro, and relate these changes with functional state of the cell. Last, the data derived from normals will be applied to our knowledge of granuloma formation in diseased individuals in an attempt to learn more about the basic cellular processes that lead to granulomatous inflammation in general, and CD4 cell redistribution to the lung in particular.
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