The B cell activation molecule, CD4O, is a member of the tumor necrosis factor receptor (TNF-R) family of molecules. Several members of this family, including CD4O, are known to deliver signals which play important roles in regulating the processes of lymphocyte activation and physiologic cell death. Another member of the family is the Fas antigen, shown to deliver signals important in mediating activation-induced apoptosis of lymphocytes. Preliminary data present our finding that overexpression of the CD4O molecule in T or B cell lines protects cells from Fas-mediated apoptosis. Expression of CD4O was sufficient for this protection; CD4O engagement was not required. Cells overexpressing CD40 remain sensitive to other mediators of apoptosis. CD40 molecules containing cytoplasmic domain mutations were not protective, implicating intracellular signaling as a mechanism. One of the major goals of this proposal will be to determine the molecular mechanisms by which CD40 expression protects cells from Fas-mediated apoptosis, and determine how CD4O and Fas signaling pathways interact. The intracellular events resulting from CD40 signaling are still largely undefined. Our preliminary findings analyzing cytoplasmic domain mutants of CD4O suggest that various downstream signals mediated by CD4O may result from multiple signaling pathways. The dependence of a number of physiologically relevant signals, occurring both immediately and later following CD40 engagement, on specific structural features of the CD40 cytoplasmic and transmembrane domains will be determined. We will also examine the molecular mechanisms by which other signals delivered during cognate T cell-B cell interactions enhance CD40-mediated signals. Finally, the role of intracellular binding proteins in mediating CD40 signals will be examined.
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