Role of TACI in B Cell Function and Transformation

Dysregulation of signaling pathways that control B cell homeostasis is likely to contribute to development of lymphoid neoplasias This application focuses on the tumor necrosis factor receptor (TNFR) family member TACl (transmembrane activator and CAML interactor) which has been implicated in B cell homeostasis. The applicant seeks to learn how it is differentially activated compared to the related receptors BCMA and BAFF-R, what signaling pathways it uses, and its role in lymphocyte proliferation and survival in normal and malignant cells. TACl was originally cloned and characterized by the applicant as an orphan receptor of unknown function. Recently, it has become of wider interest because of its newly established membership in a larger signaling network involving two ligands (APRIL and BAFF) and two other TNFR family members (BAFF-R and BCMA). BAFF (also called BLyS, THANK, TALL, and zTNF4) was first identified in 1999 as an orphan TNF homologue with B-lymphocyte stimulatory properties, and was found to bind and activate signaling through TACI. BAFF may play a role as a growth stimulator in B cell neoplasms, since dominant negative (soluble decoy) receptors based on the TACI extracellular domain have been shown to block or slow B cell tumor growth in vitro and in mice. Like TACI, BAFF-R and BCMA are expressed by mature B lymphocytes and specifically bind BAFF. BCMA (but not BAFF-R) shares with TACI the ability to bind APRIL, as well. To begin to extricate information on the physiologic role of TACI from this complex multi ligand/multi receptor system, the applicant generated a TACl knockout mouse and identified two critically important roles for the protein. First, B cells were found to hyperproliferate, accumulating to high numbers in spleen and peripheral blood of TACl-deficient mice. Second, the mutant mice demonstrated a severe defect in production of specific antibodies after immunization with T-independent type 2 (TI-2) antigens (such as bacterial polysaccharides). In contrast, others recently reported that a naturally occurring mutation in the mouse BAFF-R gene causes a severe depletion of mature B cells. It seems likely, therefore, that TACl and BAFF-R regulate B cell growth and function in opposite directions and that their differential expression and activation regulate mature B cell homeostasis. The goals of this project are to test the central hypothesis that TACI plays a negative regulatory role by blocking B cell proliferation or inducing programmed cell death, and to identify upstream and downstream regulatory mechanisms that mediate its effects. Experiments will focus on determining the mechanism of action of TACI by identifying its differential activation by different ligands, and interactions with the BAFF-R and BCMA receptors. In vitro experiments will be used to examine a potential role for TACI in programmed cell death or inhibition of proliferation. Additionally, mouse models will be used to identify effects of TACl in homeostasis and lymphoma development in vivo.