Human B cell activation antigens (ActAgs) are important cell surface structures since they are candidates for receptors for growth and differentiation factors, molecules involved in cell-cell interactions, or molecules involved in microenvirommental localization. In an attempt to identify functionally important molecules, we developed mAbs against several novel B cell activation antigens (ActAgs) and delineated their expression on activated normal and neoplastic B cells. One of these ActAgs, termed B7, is a 5OkD glycoprotein member of the Ig superfamily and is expressed on activated B cells, interferon-gamma treated monocytes, and a subset of human B cell malignancies. It is now known that B7 is the ligand for the T cell restricted Ag CD28. Ligation of CD28 with either anti-CD28 mAb or our recombinant B7 induces a key pathway of T cell activation resulting in augmented lymphokine secretion. We believe that this newly described receptor ligand pair may important for two reasons. First, T cells activated through their T cell. receptor complex require a co-stimulatory signal provided by B or other Ag presenting cells to produce lymphokines, and if not received, become tolerant. Second, B cells require a cell-cell cognate interaction delivered by the surface of activated T cells in order to exit G-O and progress through G1. Interaction of B7 with CD28 may mediate both of these events. We therefore postulate that B7 may be important in: 1) inducing Ag specific class II restricted T cell activation, and 2) interacting with the T cell surface molecule that regulates B cell G1 cycle entry, proliferation, and/or differentiation. Our objective is to determine the function of the B7 Ag on normal and neoplastic B cells. In this proposal, we plan: 1) To determine which T cell populations are capable of binding B7 and to assess the functional consequences of binding; 2) To determine whether CD28 or other T cell surface molecules induce normal and neoplastic B cells to enter the cell cycle; and 3) To determine whether B7 has a functional role in regulating the proliferation. and/or differentiation of normal and neoplastic B cells. These studies should permit us to determine the importance of the CD28:B7 receptor ligand pair in regulating T and B cell activation. Moreover, these studies may prove to be very clinically significant to our understanding B cell diseases as well as in developing novel therapeutic strategies. B7+ B cell tumors may be regulated by CD28+ T cell derived lymphokines in their microenvironment, or alternatively, CD28+ T cells may directly induce Go neoplastic B cells to enter the cell cycle. Similarly, uncontrolled expression of B7 by B cells may be associated with polyclonal B cell activation, and therefore, potentially autoimmune disease. Finally, and most importantly, inhibition of the B7:CD28 pathway may be a strategy to induce specific T cell tolerance in the context of organ transplantation.
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