Early biochemical signaling events required for activation of B lymphocytes into growth and differentiation will be studied. Role of cell surface molecules in inducing biochemical changes in B cells and in their interaction with helper T cells will be investigated. The overall goal of the project is to understand and develop methods to regulate the processes involved in antibody production by B lymphocytes. Towards this goal the relative role of phospholipase G isozymes in signaling B cells through the immunoglobulin (Ig) and the Lyb2 receptors will be examined. Experiments will focus on the differential activation of the phospholipase G isozyme by protein tyrosine phosphorylation. Next the nature of the G protein involved in signal transduction through lg and presumably through the Lyb2 receptors will be identified. A novel approach of inhibiting putative G protein expression with specific antisense oligonucleotides and measuring the effect on calcium mobilization induced by anti-lg and anti-Lyb2 will be employed. The hypothesis that some (TH1) if not all helper T cells will employ the Lyb2 mediated pathway to activate B cells will be tested by studying the effect of antibodies to GD5 and Lyb2 on contact dependent T cell mediated B lymphocyte activation. The role of interaction between CD5 and Lyb2 in B cell growth responses will be investigated using soluble GD5-lg and GD72- Lyt2 molecules. The costimulatory role of Lyb2 in B cell activation will be studied using an anti-lg or immune complex induced B cell tolerance model. Also, the role of heat stable antigen and two molecules defined by monoclonal antibodies (generated in my laboratory) in T dependent B lymphocyte activation will be assessed. Finally signaling mechanisms employed in T cell contact dependent B cell activation will be evaluated by measuring changes in calcium levels in B cells by means of flow cytometry and by studying the effects of agents that affect calcium mobilization. Wild type and la-ve BKS2 mutant B cell lymphoma cells will be employed to study the signaling role of class 11 molecules. These studies should provide a rational basis to develop methods for stimulation as well as~down regulation of antibody responses in infection and autoimmunity.
Showing the most recent 10 out of 54 publications
