SIGNAL TRANSDUCTION BY IGM IN B LYMPHOCYTES

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Immunoglobulin is the B cell antigen receptor that is responsible for detecting foreign antigens and triggering a cascade of events whose end result is specific antibody production. Despite the central role of receptor immunoglobulin in the generation of immune responses, little is known about the mechanism by which this receptor produces a signal. Progress in understanding the mechanism of signaling by the immunoglobulin receptor has been hindered by two important features of this receptor. First the intracytoplasmic domain of the receptor is composed of three amino acids that offer no specific clues about the mechanism of receptor function. The second impediment to understanding receptor immunoglobulins is that they are associated with several other polypeptides on the cell surface to form a multi-subunit structure. Two of these receptor associated polypeptides MB-1, and B29 have been implicated in receptor assembly and cell surface transport, In addition, both MB-1 and B29 are rapidly phosphorylated upon receptor crosslinking, but the functional role of the IgM-associated proteins is poorly defined. We have recently succeeded in reconstituting receptor immunoglobulin function by transfecting cloned receptor components into T cells and macrophages, Although these experiments have defined the functional requirements for the production of an immunoglobulin antigen receptor in heterologous cells, they do not directly address the problem of antigen receptor function in B cells. The long range goal of the proposed research is to elucidate the molecular requirements for signal transduction by membrane anchored immunoglobulin in B lymphocytes. The working hypothesis is that B29, and MB1 are involved in signal transduction in B cells, and that the signaling apparatus of T and B cells is structurally homologous. The first part of the project will be to establish B cell lines that express transfected immunoglobulin receptors. For this purpose. we will use B cell lines that lack several receptor components. In the second part of the project we will examine the structural features of MB1 and B29 required to produce increased tyrosine phosphorylation, calcium mobilization, inositol turnover and IL-2 secretion in response to receptor crosslinking. These studies have potential implications for understanding how an antigenic stimulus triggers the generation of humoral immunity.