The spatial-temporal interactions of CD45 with the B cell receptor and regulatory roles in intracellular signaling (B45)

Abstract

Abstract Background: CD45, a membrane-bound phosphatase, has been shown to enhance and inhibit intracellular signaling in many different immune cells including B lymphocytes. However, the mechanisms of CD45 have not been fully described. Objectives: To build a computational model for B cell signaling in order to investigate the role of CD45 in the initiation of intracellular signaling upon B cell receptor ligation with antigen and the spatial-temporal interactions with the B cell receptor and signaling protein tyrosine kinases. Methods: Kinetic Monte Carlo stochastic simulations will be used with probabilistic rate constants mapped to experimentally measured parameters. Simulation results will be tested in vitro. Anticipated results: It will be shown that without a binding partner, CD45 will be pushed out early in the formation of the B cell immunological synapse. For the duration that CD45 interacts with intracellular Src family kinases (SFK) in close proximity of clustered B cell receptors, there is sufficient activation of SFK to initiate the signaling cascade. It will also be shown that it is critical for CD45 to be pushed out from the immunological synapse away from BCR and the SFK so that non-phoshorylated BCR should be internalized and used for antigen capture and presentation on MHC II. 530 754-5739