Thymus-independent class switch recombination is affected by APRIL

The tumour necrosis factor (TNF) family member a proliferation-inducing ligand (APRIL) is implicated in various B-cell processes, such as class switch recombination, plasma cell differentiation and plasma cell survival. This was suggested from initial studies analysing B-cell responses in APRIL-deficient and transgenic mice, and mice deficient for the TNF receptors of APRIL, transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen. Here, we present additional evidence for the importance of APRIL in thymus-independent (TI) B-cell responses, using APRIL-deficient and transgenic mice. APRIL-deficient mice show an impaired immunoglobulin A (IgA) response towards TI B-cell antigens, whereas APRIL transgenic mice show exaggerated TI B-cell responses. Moreover, antibody titres to TI antigens were sustained in APRIL transgenic mice for a long time and even increased up to 75 days in the case of IgA against 4-hydroxy-nitrophenacetyl-lipopolysaccharid

Serpins prevent granzyme-induced death in a species-specific manner

Expression of serine protease inhibitors (serpins) is one of the mechanisms used by tumour cells to escape immune surveillance. Previously, we have shown that expression of serpins SPI-6 and SPI-CI, respectively, renders tumour cells resistant to granzyme B (GrB)-mediated death and granzyme M (GrM)-mediated death. To obtain better insight into the interaction between serpins and their target proteases, we investigated the roles of protease inhibitor (PI)-9 and SPI-6 in the resistance to GrB-mediated and CD95-mediated death in further detail. Neither human PI-9 nor its murine orthologue SPI-6 was capable of preventing CD95-induced apoptosis in murine or human cells, indicating that these serpins do not inhibit the activation of apical caspases in this pathway. High expression of PI-9 or SPI-6 did prevent apoptosis induced by human GrB. Strikingly, only SPI-6, and not PI-9, was capable of inhibiting murine GrB, suggesting that a difference in enzymatic specificity exists between the mouse and the human granzymes. In agreement with this suggestion, murine GrB was clearly less effective in inducing apoptosis in human cells. Similar species specificity was also observed for SPI-CI and GrM when either their capacity to associate or the effectiveness of GrM-induced cytotoxicity was analysed. Our findings therefore indicate a species diversity that has a clear effect on mixed in vitro effector target setting

The proteoglycan (heparan sulfate proteoglycan) binding domain of APRIL serves as a platform for ligand multimerization and cross-linking

A proliferation-inducing ligand (APRIL) (also known as TALL-2 and TRDL-1) is a member of the tumor necrosis factor (TNF) superfamily that has tumorigenic properties but is also important for the induction of humoral immune responses. APRIL binds two TNF receptors: transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA) as well as heparan sulfate proteoglycans (HSPGs). The aim of this study was to clarify the role of the HSPG interaction in canonical APRIL signaling, because it has been proposed to act as a docking site and also to play a role in direct signaling. In this study, we generated point mutants of soluble APRIL that lack either the capacity to bind HSPGs or TACI and BCMA and then tested the function of these mutants in mouse B-cell assays. In contrast to previous reports, we found that APRIL alone is sufficient to costimulate B-cell proliferation and drive IgA production and does not require artificial antibody cross-linking. We found no evidence that APRIL requires signaling through HSPGs but, notably, were able to show that binding of APRIL to HSPGs is crucial for mediating natural APRIL cross-linking to allow for optimal activation of murine B cells.-Kimberley, F. C., van Bostelen, L., Cameron, K., Hardenberg, G., Marquart, J. A., Hahne, M., Medema, J. P. The proteoglycan (heparan sulfate proteoglycan) binding domain of APRIL serves as a platform for ligand multimerization and cross-linking. FASEB J. 23, 1584-1595 (2009