APRIL modulates B and T cell immunity

Abstract

The TNF-like ligands APRIL and BLyS are close relatives and share the capacity to bind the receptors TACI and BCMA. BLyS has been shown to play an important role in B cell homeostasis and autoimmunity, but the biological role of APRIL remains less well defined. Analysis of T cells revealed an activation-dependent increase in APRIL mRNA expression. We therefore generated mice expressing APRIL as a transgene in T cells. These mice appeared normal and showed no signs of B cell hyperplasia. Transgenic T cells revealed a greatly enhanced survival in vitro as well as enhanced survival of staphylococcal enterotoxin B-reactive CD4 + T cells in vivo, which both directly correlate with elevated Bcl-2 levels. Analysis of humoral responses to T cell-dependent antigens in the transgenic mice indicated that APRIL affects only IgM but not IgG responses. In contrast, T cell-independent type 2 (TI-2) humoral response was enhanced in APRIL transgenic mice. As TACI was previously reported to be indispensable for TI-2 antibody formation, these results suggest a role for APRIL/TACI interactions in the generation of this response. Taken together, our data indicate that APRIL is involved in the induction and/or maintenance of T and B cell responses.

TGF-β1 Stimulates Mouse Macrophages to Express APRIL through Smad and p38MAPK/CREB Pathways

“…Effect of TGF-β1 on APRIL expression by mouse macrophages It is increasingly clear that APCs directly affect B cells: macrophages regulate B-cell responses, and TNF-like ligands APRIL and BAFF expressed by macrophages play an important role in B-cell activation and differentiation (Stein et al, 2002). Ig isotype switching is a critical event in B-cell differentiation, and TGF-β1 is a specific switching factor for the IgA and IgG2b mouse isotype (Kim and Kagnoff, 1990;McIntyre et al, 1993).…”

“…Further, B cell-activating factor (BAFF), which belongs to the TNF family, and a proliferationinducing ligand (APRIL), are expressed by macrophages and DCs, and are critical factors for the growth and survival of both normal and malignant B cells (Fagarasan and Honjo, 2000;Litinskiy et al, 2002). Interestingly, APRIL is known to increase IgA and IgM but not IgG responses to T cell-dependent antigens (Stein et al, 2002). More specifically, APRIL is known to exclusively influence IgA isotype regulation: IgA production increases in APRIL transgenic mice (Stein et al, 2002), and conversely, IgA class switching recombination is impaired in APRIL-deficient mice (Castigli et al, 2004).…”

“…Interestingly, APRIL is known to increase IgA and IgM but not IgG responses to T cell-dependent antigens (Stein et al, 2002). More specifically, APRIL is known to exclusively influence IgA isotype regulation: IgA production increases in APRIL transgenic mice (Stein et al, 2002), and conversely, IgA class switching recombination is impaired in APRIL-deficient mice (Castigli et al, 2004).…”

The anti‐apoptotic factor Bcl‐2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

“…B cell survival and emergence of marginal zone B cells are probably only dependent on BAFF and BAFF-R, because TACI -/-and BCMA -/-mice have mature B cell and marginal zone B cell populations [3,9]. T-independent type-2 responses may, however, depend on both BAFF and/or APRIL, because they are mediated, at least in part, through TACI [9,35] and are enhanced in APRIL-Tg mice [36]. In addition, both BAFF and APRIL induce CD40L-independent isotype switch in human peripheral blood B cells in vitro [7].…”

Intrarenal production of B-cell survival factors in human lupus nephritis

“…11,12 In contrast, APRIL-transgenic mice manifest only subtle abnormalities. 13 In lupus mouse models, circulating BLyS levels were found to be elevated 12 and interventions into the APRIL/BLyS system ameliorated proteinuria and renal inflammation. 12,14,15 Consistently in human systemic lupus erythematosus, serum as well as blood mRNA levels of APRIL and BLyS were found to be elevated.…”