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.

BLyS and APRIL in rheumatoid arthritis

“…Whereas BCMA is mostly expressed on B cells, TACI also regulates T cell function (28). Also, TACI -/-mice develop a fatal lymphoproliferative syndrome, suggesting that APRIL and BLyS have immunoregulatory effects beyond supporting B cell differentiation and antibody production.…”

“…T cell-dependent humoral responses revealed an increase in serum IgM, while serum IgG levels remained unaffected. T cell-independent type II humoral responses were also enhanced, manifested by elevated IgM and IgG serum levels (28). In contrast, APRIL -/-mice present with normal development, maturation, distribution, and function of T and B lymphocytes (29).…”

Untitled

“…Moreover, differentiation of ISCs is affected by continued stimulation by B cell activating factor (BAFF/BlyS/TNFSF13B) through two of its receptors – B cell maturation antigen (BCMA) and BAFF receptor (BAFF-R) – in a T dependent (TD) manner [9], and through its third receptor – transmembrane activater and CAML interacter (TACI) – in a T independent (TI) manner [10-13]. Of note, BAFF is located in an SLE susceptibility locus (13q32-34) [14-17] and has been found to be elevated in the serum of patients with active SLE [18,19]. …”

“…Interestingly, mice that over-express BAFF [32-34] exhibit an autoantibody mediated, lupus like disease, and BAFF (13q32-34) is encoded in human genetic regions [14-17] that contain SLE susceptibility loci. Moreover, soluble, biologically active BAFF has been found to be elevated in the serum of a fraction of patients with active SLE [18,19].…”

“…Moreover, mice transgenic for APRIL/TALL2/TNFSF13, the TACI and BCMA ligand, had an exaggerated serum IgM response to TI antigens [39]. In mice transgenic for phosphorylcholine specific immunoglobulin, soluble BAFF derived from Streptococcus pneumoniae loaded splenic dendritic cells or peritoneal macrophages, respectively, drove antigen induced survival and IgM plasmablast differentiation from marginal zone or B1 B cells in a TACI dependent manner.…”