STUDIES OF RECEPTOR IMMUNOGLOBULIN MEDIATED SIGNALLING

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While an absolute requirement for receptor immunoglobulin mediated signaling has yet to be demonstrated for the activation of resting B cells, evidence from a variety of sources suggests that in at least some cases, crosslinking of B cell surface Ig is a prerequisite for clonal expansion and differentiation. If ligand induced receptor Ig mediated signalling results in relevant signals for activation, one would expect that such signaling would drive the resting, GO-B cell to traverse specific restriction points along the activation pathway. Such B cells would enter a state of commitment for activation, dependent presumably, on subsequent secondary signals for proliferation and differentiation. Definition of the role of receptor Ig generated signaling at the molecular level would greatly enhance our understanding of the critical signals required for activation of GO stage B cells as well as to further our understanding of receptor mediated signaling and activational commitment points for cell growth control in general. The objective of this proposal is to investigate the role and mechanism of receptor Ig mediated signaling during ligand driven B lymphocyte activation. To accomplish this, we propose to study specific molecular changes resulting from ligand-receptor immunoglobulin interaction and to assess at the functional level, to what extent these changes represent specific commitment points in the B cell activation process. Specifically, we will explore the role of ligand induced receptor crosslinking in the stimulation of increased expression of I-A alpha and I-E beta genes as well as the c-myc proto-oncogene. Stimulated increases in expression of each of these genes has been implicated as important control points along the B cell activation pathway in mitogen systems and are likely to represent critical commitment points in ligand induced B cell stimulation as well. Once establishing a causal relationship between receptor Ig occupancy or crosslinking and expression of these gene products, functional studies will be undertaken to demonstrate the relevance of increased I-A alpha, I-E beta and c-myc expression towards more conventional hallmarks of B cell activation such as proliferation and immunoglobulin secretion. In addition, we propose to investigate the mechanism(s) operative in transducing receptor Ig generated signals across the plasma membrane to facilitate increased I-A alpha, I-E beta and c-myc gene expression. In particular, we will define the role of protein kinase C in the signal transduction pathway as well as protein-protein associations that may be important in signaling.