TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation

We and others recently reported tumor necrosis factor (TNF) and apoptosis l igand-related leukocyte-expressed ligand 1 (TALL-1) as a novel member of th e TNF ligand family that is functionally involved in B cell proliferation. Transgenic mice overexpressing TALL-1 have severe B cell hyperplasia and lu pus-like autoimmune disease. Here, we describe expression cloning of a cell surface receptor for TALL-1 from a human Burkitt's lymphoma RAJI cell libr ary. The cloned receptor is identical to the previously reported TNF recept or (TNFR) homologue transmembrane activator and calcium modulator and cyclo philin ligand (CAML) interactor (TACI). Murine TACI was subsequently isolat ed from the mouse B lymphoma A20 cells. Human and murine TACI share 54% ide ntity overall. Human TACI exhibits high binding affinities to both human an d murine TALL-1. Soluble TACI extracellular domain protein specifically blo cks TALL-1-mediated B cell proliferation without affecting CD40- or lipopol ysaccharide-mediated B cell proliferation in vitro. In addition, when injec ted into mice, soluble TACI inhibits antibody production to both T cell-dep endent and -independent antigens. By yeast two-hybrid screening of a B cell library with TACI intracellular domain, we identified that, like many othe r TNFR family members, TACI intracellular domain interacts with TNFR-associ ated factor (TRAF)2, 5, and 6. Correspondingly, TACI activation in a B cell . Line results in nuclear factor KB and c-Jun NH2-terminal kinase activatio n. The identification and characterization of the recaptor for TALL-1 provi des useful information for the development of a treatment for B cell-mediat ed autoimmune diseases such as systemic lupus erythematosus.