Roose-Girma, S. vivo humoral responses to antigenic challenge. These data indicate that APRIL is dispensable in the Leupeptin hemisulfate mouse for proper development. Thus, BLyS may be capable of fulfilling APRIL’s main functions. Various aspects of the development and activity of the mammalian immune system are regulated by proteins that belong to the tumor necrosis factor (TNF) ligand family (reviewed in references 1, 11, 15, 36, and 43). Most members of the TNF ligand family are Leupeptin hemisulfate type II transmembrane proteins with the receptor-binding motif located at their C terminus. Except LT, which is expressed only as a soluble molecule, TNF family members are expressed as cell surface proteins acting in a juxtacrine and autocrine manner. Proteolytic processing of some of the ligands generates their corresponding soluble forms. The majority of proteins of the TNF receptor family are composed of type I transmembrane molecules. Many of these receptors also exist in soluble forms generated by proteolytic cleavage of the cell surface protein or transcribed by alternative splicing mechanisms from the genes encoding the full-length receptors. The ligand-binding motif of the TNF receptor family consists of tandem cysteine-rich domains of about 40 amino acids in length. Each cysteine-rich domain contains several cysteines (typically six) and certain other residues in conserved positions. APRIL (a proliferation-inducing ligand, also known as TRDL-1, TALL-2 [12, 35], and TNFSF13A) is a member of the TNF family that has been Leupeptin hemisulfate shown to be capable of inducing the proliferation of certain tumor cell lines in vitro and in vivo (9). Together with a related member of the TNF family, BLyS (B-lymphocyte stimulator, also known as BAFF, TALL-1, zTNF4, THANK, and TNSF13B) (22, 23, 32, 35), APRIL shares two common receptors, TACI and BCMA (21, 29, 40, 45). However, unlike APRIL, BLyS also binds to BR3 (BLyS receptor 3 or BAFF-R), the least-conserved member of the TNF receptor family (39, 48). Both APRIL and BLyS are expressed by macrophages, monocytes, dendritic cells, and T cells (25, 32, 35, 37). Both ligands exist in cell surface as well as soluble forms. Like most other TNF family members, soluble BLyS is created by cleavage of a transmembrane cell surface protein (18, 22, 32). In contrast, soluble APRIL is produced in the Golgi apparatus within the cell by a furin convertase (16). Furthermore, the transmembrane form of APRIL (named TWE-PRIL) is an unusual fusion product of two alternatively spliced RNAs, composed of exons encoding intracellular and transmembrane domains from the neighboring family member [also called or (4, 20)] and exons from encoding the extracellular part of the molecule (28). BCMA, TACI, and BR3 are type III transmembrane proteins, lacking N-terminal signal sequences. BCMA and TACI contain intracellular TRAF binding motifs (reviewed in reference 17). The signaling mechanisms of these receptors are not fully characterized; however, they activate the NF-B and mitogen-activated protein kinase pathways (reviewed in reference 17). All three receptors are expressed on B cells, while TACI and BR3 are also detected on the surface of some T cells (14, 39, 41, 46, 48). While several reports document direct involvement of BLyS, TACI, and BR3 in regulating the development PIK3C2B and function of B cells in vivo (reviewed in reference 17), the role of APRIL in immune regulation is not well defined. Alteration in the expression of BLyS or BR3 in the mouse (by gene knockout or naturally occurring mutation, respectively) leads to diminished numbers of mature B cells due to a block at the T1 stage of development (7, 31, 40, 49). In contrast, knockout of results in accumulation of B cells, particularly pronounced in older mice with homogeneous genetic background (34). Elevated levels of BLyS in transgenic mice upregulate B-cell activity, leading to the development of a lupus-like autoimmune disorder (8, 13, 18). Humans with severe B-cell disorders.