Engagement of CD40 by its ligand (CD40L), a molecule transiently expressed on the surface of activated CD4 plus T cells, provides potent activation and survival signals for B lymphocytes. In contrast, the Fas antigen transmits signals which initiate programmed cell death (apoptosis) following engagement by Fas ligand (FasL), a molecule also selectively expressed by activated CD4 plus T cells. Our laboratory, and those of others, have recently defined a novel immunoregulatory pathway in which signals delivered by the B cell activation/survival molecule CD40 and the Fas molecule which mediates apoptosis are linked in the process of CD4 plus T cell-induced B cell activation. Fas antigen expression is unregulated following CD40 ligation on both normal and malignant human B cells including Burkitt's lymphoma (BL) cells (the malignant counterpart of germinal center B cells). Following CD40 ligation normal B cells and Epstein Barr Virus (EBV) negative BL cells are rendered susceptible to Fas-mediated apoptosis. In contrast, EBV positive BL specimens are resistant, suggesting that latent EBV infection allows BL tumor cells to escape Fas antigen-dependent immunosurveillance. The role of EBV as a cofactor in development of BL, suggests that this escape mechanism may be of pathogenic significance. The studies proposed are designed to explore CD4 plus T cell control of human B cell activation/deletion, with an emphasis on Fas antigen-dependent destruction of BL B cells and the role of EBV in promoting resistance to this immunoregulatory pathway. Specifically, we will analyze: 1. Parameters which govern CD4 plus T cell induced Fas antigen expression and Fas mediated apoptosis of normal and Bl B cells, including: 1) the functional subset of CD4 plus T cells which delivers the CD40 signal. Th1 versus Th2; 2) the effect of sig signaling (signal 1); 3) the role of cytokines; and 4) the need for additional B cell surface antigen engagement by T cell ligands. 2. The control of Fas-dependent apoptosis in EBV plus BL B cells. 3. The effect of EBV genes which impact B cell apoptosis on intracellular signaling pathways initiated by sig crosslinking, CD40 engagement, and Fas ligation. These studies are designed to both enhance our understanding of CD4 plus T cell-mediated regulation of the normal humoral immune system in man and provide a rationale for novel immunotherapeutic strategies in the treatment of B cell malignancies.
