TACI was originally cloned as a novel Tumor Necrosis Factor Receptor-family member, based on its ability to interact with the intracellular signaling protein CAML. TACI is present on the surface of resting mature B cells. Although the physiological significance of the protein is not yet known, signaling studies suggest that it activates NF-kB and NFAT transcription factors in a heterologous system. Recently, others have identified two potential ligands for TACI, the B cell growth factors BlyS (also known as zTNF4, TALL1, THNK, and BAFF) and APRIL, both of which are homologues of Tumor Necrosis Factor. It seems reasonable to predict that TACI may act as a growth stimulatory receptor, given the known actions of its proposed ligands. The picture is complicated, however, by the finding that another TNFR-homogue, BCMA, is equally competent to bind BlyS and APRIL. It is not clear whether cross-linking of the receptors by BlyS or April might activate similar or different signal transduction pathways. In addition, it is not yet known whether TACI is expressed on B-cell derived malignancies, and if so, whether it contributes to the transformed phenotype. In order to begin to sort out the possible occurrence and significance of TACI in B cell malignancies, we have developed a highly specific monoclonal antibody to the extracellular domain of the protein. The antibody detects human TACI protein by Western blotting and by flow cytometry of intact cells, thus providing a new reagent that can be used to reproducibly quantitate TACI expression on cells. Analysis of human cell lines revealed moderate levels of TACI expression on mature B-cell lymphomas, and enhanced expression on EBV-immortalized lymphoblastoid cells. A subset of myeloma cell lines also demonstrated TACI expression, while immature early pre-B ALL cell lines did not express the protein. Since NF-kB activation has been tied to increased resistance to apoptosis, we asked whether TACI retains signaling ability in these cells. Stimulation of TACI using cross-linked monoclonal antibodies induced a cytoplasmic-to-nuclear translocation of the p65 subunit of NF-kB, indicating the TACI-NF-kB signaling pathway is intact in these cells. These data suggest that TACI functions on the cell surface of some lymphoma cells to enhance their resistance to apoptosis, and raise the possibility that blocking reagents (such as a TACI decoy-receptor) could possess therapeutic potential for some B-cell malignancies.
|Original language||English (US)|
|Issue number||11 PART I|
|State||Published - Dec 1 2000|
ASJC Scopus subject areas
- Cell Biology