Tumor necrosis factor (TNF) ligand family members are synthesized as transmembrane proteins, and cleavage of the membrane-anchored proteins from the cell surface is frequently observed. The TNF-related ligands APRIL and BLyS and their cognate receptors BCMA/TACI form a two ligand/two receptor system that has been shown to participate in B-and T-cell stimulation. In contrast to BLyS, which is known to be cleaved from the cell surface, we found that APRIL is processed intracellularly by furin convertase. Blockage of protein transport from the endoplasmic reticulum to the Golgi apparatus by Brefeldin A treatment abrogated APRIL processing, whereas monensin, an inhibitor of post-Golgi transport, did not interfere with cleavage of APRIL, but blocked secretion of processed APRIL. Thus, APRIL shows a unique maturation pathway among the TNF ligand family members, as it not detectable as a membrane-anchored protein at the cell surface, but is processed in the Golgi apparatus prior to its secretion.

Death receptors belonging to the tumor necrosis factor receptor family (e.g., Fas/CD95, TNFR1, TRAIL-R1, TRAIL-R2, TRAMP/DR3, and DR6) play an important role in the regulation of lymphocyte homeostasis (35,42,44). Upon encounter of specific antigenic peptides presented by antigenpresenting cells, T cells become activated and enter the cell cycle. Concomitantly with proliferation, T cells differentiate into effector cells that are either cytolytic or able to provide help to B lymphocytes. Once the effector cells have successfully performed their prescribed function, the expanded pool of antigen-specific T-cell clones needs to be reduced to its original size. Both for the effector function of cytolytic T cells and in the elimination of expanded T cells, cell death signals transmitted by Fas/CD95 are of key importance (30). This is underscored by the observation that mice and humans lacking a functional Fas receptor or Fas ligand develop a lymphoproliferative disease and systemic autoimmunity accompanied by the production of autoantibodies (12,40,52,59).As with all death receptors, the prototypic death receptor Fas/CD95 contains within its cytoplasmic tail a 60-amino-acid death domain (DD) motif (35,44). Upon activation of Fas by its ligand, the DD undergoes homotypic interaction with a DD in the adaptor protein FADD, which then recruits the initiator caspase 8 via their mutual N-terminal death effector domains (DED) (3). A high local concentration of caspase 8 zymogens is thought to facilitate self-processing and cleavage to the active enzyme (34). Activated caspase 8 then initiates apoptosis by cleavage of the downstream effector caspases 3, 6, and 7 (10).A number of gammaherpesviruses and molluscipoxviruses encode a molecule termed FLIP (FLICE inhibitory protein) that can inhibit FasL-induced cell death (5, 53). v-FLIP resembles caspase 8 in containing two DED but lacks the enzymatic C-terminal portion. As such, v-FLIP can be recruited into the death-inducing signaling complex (DISC) of Fas, thereby competing with recruitment of caspase 8 to FADD. In this manner, v-FLIP may function to promote viral persistence and dissemination by inhibiting death receptor-mediated elimination of infected cells (56). A mammalian cellular homologue (c-FLIP) has been described that exists in at least two splice variants, c-FLIP S and c-FLIP L (15, 16, 20-22, 38, 47, 49). Like v-FLIP, the 26-kDa c-FLIP S has two DED and functions in a similar manner to inhibit death receptor-induced apoptosis (22). The full-length 55-kDa form of c-FLIP (c-FLIP L ) shows overall structural homology to caspase 8. It contains two DED that interact with FADD but bears a mutation in the caspase-like domain that renders it enzymatically inactive. Following Fas ligation, both c-FLIP L and caspase 8 are recruited into the DISC and are subsequently partially cleaved. The affinity for FADD of the c-FLIP L /caspase 8 heterodimer appears to be considerably greater than that of the caspase 8 homodimer; therefore, the ratio of c-FLIP L to caspase 8 is critical ...

Immunization of mammals with irradiated malaria sporozoites protects from a subsequent contact with the parasite. Protective immunity is directed against the pre‐erythrocytic stages of the parasite, sporozoites and liver stages. Specific antibodies neutralize part of the infectious sporozoites injected by the mosquito vector, while liver stages are the target of a cellular immune response which is mediated by T cells. In this study, we evaluated the T‐cell dependent protection induced by the injection of P. berghei irradiated sporozoites and the contribution of perforin and of the receptor/ligand system CD95/CD95L, two T cell‐dependent mechanisms known to mediate elimination of target cells. Wild type, perforin deficient, CD95 mutant, CD95L mutant and perforin deficient/CD95L mutant mice were immunized with P. berghei irradiated sporozoites and submitted to a challenge with infectious sporozoites. All mice immunized with P. berghei irradiated sporozoites were protected against a sporozoite challenge, including perforin deficient/CD95L mutant animals. These results indicate that T cells do not kill malaria‐infected hepatocytes via one of the known pathways, but rather that activated parasite‐specific T cells produce cytokines which activate in cascade other mechanisms responsible for the intracellular elimination of the parasite.

The tumour necrosis factor (TNF) family is intimately connected to the regulation of cellular pathways. A PRoliferation-Inducing Ligand (APRIL) is a rather new member of that family, named for its capacity to stimulate the proliferation of tumour cells in vitro. Subsequent publications also called this ligand TRDL-1 or TALL-2, respectively. APRIL and B-lymphocyte stimulator (BLyS; also termed BAFF, TALL-1, THANK, zTNF4) form a new subfamily of TNF-like ligands that are expressed in haematopoietic cells. Both ligands can bind the two members of the TNF receptor family, namely the transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), as well as Bcell maturation antigen (BCMA). BLyS has recently been the subject of several reviews (for an extensive review, see Mackay et al.). The present review will thus focus on APRIL, and discuss BLyS only briefly for the sake of clarity.