The laboratory is involved in studies of two proteins that are encoded by genes that are selectively expressed by immature murine skin-derived dendritic cells. One of the proteins is a C-type lectin termed """"""""Langerin"""""""" because of its restricted expression in Langerhans cells, a population of dendritic cells that are found exclusively in stratified squamous epithelia. Although Langerin is known to be expressed on cell surface and localized to unique endocytotic vesicles termed Birbeck granules, its physiologic ligands are only beginning to be identified and its function is incompletely characterized. We have generated soluble forms of recombinant Langerin that retain mannan-binding activity and are utilizing these probes to identify and characterize Langerin ligands and thus further define Langerin's role in immunophysiology. One area of investigation focuses on identification of Langerin ligands that are associated with microbial pathogens and definition of the role of this protein as an important pathogen recognition receptor. Another area of investigation focuses on characterization of endogenous Langerin ligands. Preliminary results suggest that Langerin binds selectively to several extracellular matrix molecules. Experiments to independently verify these results, and to determine their significance, are in progress. MFG-E8 is a second protein that is under active investigation. In accordance with our prediction and consistent with its avb3 integrin- and phosphatidyl serine binding activity, others have demonstrated that MFG-E8 can mediate the uptake of apoptotic cells by macrophages. We have generated several MFG-E8 mouse mutants to determine if MFG-E8 has a non-redundant role in apoptotic cell uptake in vivo and, further, to determine if MFG-E8 is involved in cross presentation of antigens that are not expressed by antigen presenting cells. Because MFG-E8 is homologous to del1, a protein expressed exclusively by endothelial cells in embryos and in tumors, we are also defining the role that MFG-E8 may play in angiogeneis and tumorigenesis. The final project area in the laboratory involves testing the feasibility of using T cell receptor proteins expressed by clonal T cell malignancies as tumor antigens in vaccines. DNA-based (genetic vaccination) strategies are being emphasized because of concerns regarding the practicality of patient-specific therapies. Both alpha virus-based (self-replicating) as well as conventional eukaryotic expression vectors are being utilized. A reproducible model involving subcutaneous growth of T cell lymphomas in mice has been established in the laboratory. cDNAs encoding T cell receptor alpha and beta chains from this murine T cell lymphoma have been cloned, sequenced and introduced into relevant vectors, and testing of vaccination regimens has begun.
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