The studies proposed in Project 1 are designed to define the structure and binding characteristics of a lymphokine, Lymphocyte Chemoattractant Factor (LCF) to its receptor CD4. LCF was originally identified and characterized by our laboratory in 1982. Several important discoveries about LCF have heightened its potential importance. Briefly summarized, LCF binds specifically to human CD4, inducing rises in intracellular levels of Ca and inositol triphosphate. Subsequently, motile responses and upregulation of MHC Class II surface antigens (HLA-DR) and IL2 receptors occur. Despite these activation events following exposure to LCF, no IL2 secretion occurs and no DNA synthesis takes place. Thus, LCF is, by definition, a CD4+ T cell competence-type growth factor, and it is a natural ligand for CD4. Therefore, CD4 may participate in multiple ways in the T cell inflammatory process, now including amplification of the accumulation of CD4+ T cells and monocytes via both chemoattractant and growth factor activity. In order to understand the structure-function binding relationship between LCF and CD4, and understand this ligand's CD4-related membrane signal transduction complex, we propose, in this Project, to complete cDNA and genomic cloning of LCF, characterize its specific binding site on CD4, identify other membrane proteins associated with CD4 signalling, (including a Pertussis Toxin G protein, phosphokinases activity and other T cell membrane associated proteins) and complete the evaluation of the LCF-CD4 signal by measurements of Protein Kinase C activity. We believe these studies will provide new insights into the function of a major differentiation antigen, CD4. Project 1 interacts directly with each other Project of the SCOR by providing rLCF, LCF peptides and antibodies to LCF for the studies of CD4 function on eosinophils (Project 2), and monocytes and alveolar macrophages (Project 3) and on the cell cycle events and affects on CD4+ T cell transmigration from blood to lung with Project 4.
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