BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells

Abstract

IntroductionB cell-activating factor belonging to the TNF family (BAFF) has emerged as an important regulator of B-cell homeostasis and survival: it acts alone or in combination with B-cell receptor (BCR), IL-4, or CD40 ligands. 1-4 BAFF binds 3 different TNF receptors: BCMA (B-cell maturation), 5,6 TACI (transmembrane activator and CAML interactor), 7 and BAFF-R/BR3 (BLys receptor 3). 8 A highly similar homolog (called "a proliferation-inducing ligand" or APRIL) 1 also binds TACI and BCMA but not BAFF-R. 9 BCMA, TACI, and BAFF-R are mostly found on B lymphocytes, [10][11][12] whereas BAFF-R is also present on a subset of T cells. 11,13 Accordingly, BAFF produced by antigen-presenting cells provides T-cell costimulation. 13 The BAFF/BAFF-R pair is essential for survival of immature T2, B2, and marginal zone (MZ) B cells, [14][15][16] but not for that of B1 cells, 17,18 whereas TACI exerts a negative control over 20 BCMA has no obvious effect on mature B-cell survival, but is important for long-term plasma cell biology 10,12 and antigen presentation. 21 BAFF-or BAFF-R-deficient mice form only rudimentary germinal centers (GCs) and produce low levels of IgG in response to T-dependent (TD) antigens. 22,23 In contrast, TACI-deficient mice display an impaired response to type II T cell-independent antigens, suggesting that TACI is required for B1 cell survival. 24 BAFF-R and TACI provide signals for isotype switching toward IgG and IgE, but the switch to IgA is mainly controlled by TACI. 17,25 Many BAFF transgenic mice show signs of autoimmunelike diseases, 2,26 whereas aged APRIL-transgenic mice display a progressive expansion of B1 cells infiltrating the peritoneum and lymphoid organs. 27 These various observations support a major role for the TACI/APRIL and BAFF-R/BAFF pairs in B1 and B2 cell physiology, respectively.Like CD40L, BAFF mainly promotes NF-B and MAPK activation. 28,29 Triggering BAFF-R results in activation of NF-B2 and NF-B1 pathways, whereas triggering BCMA and TACI only activate the NF-B1 pathway. 7,9,28,30,31 Different sets of MAPK and transcription factors are activated downstream from BCMA, TACI, and BAFF-R. 29,32,33 In particular, it has been shown that p38MAPK but not ERK is stimulated early after BAFF-R triggering. 34 Lymphocyte recirculation, which is essential for maintaining an effective immune system, is tightly regulated by the expression of adhesion molecules, chemoattractant receptors, and environmental cytokines. 35,36 Trafficking of human naive and memory B cells is mainly orchestrated by CXCR4/CXCL12, CXCR5/CXCL13, and CCR7/CCL21 (or CCL19) pairs. 37,38 The efficiency of the humoral response depends on the chemotactic response of mature B cells that is modulated by BCR-and IL-4-receptor triggering and CD40/CD40L interactions. 37,[39][40][41][42] In particular, BCR triggering enhances the chemotactic response of naive B cells to CCL21 but decreases that to CXCL13. In contrast, CD40L enhances the migration of memory B cells to CXCL13 without modifying that of CXCL12, CCL21, or CCL19. ...

Local BAFF gene silencing suppresses Th17-cell generation and ameliorates autoimmune arthritis

“…We show that administration of LV-shBAFF in the CIA mice suppresses the expression of proinflammatory cytokines, such as IL-6, IL-1␤, and IL-23, in joint tissue, an effect possibly contributed predominantly by its inhibition on leukocyte infiltration. In addition, the significant down-regulation of chemokine levels in joint tissues after LV-shBAFF treatment may furthermore suppress the chemotaxis of both T and B cells, a notion reinforced by recent findings that CXCL13 and BAFF synergistically enhance B-cell chemotaxis (29). BAFF genesilenced DCs show defective IL-6 production and display severely impaired capacity in inducing Th17-cell generation in vitro.…”

Mesenchymal stromal cells protect mantle cell lymphoma cells from spontaneous and drug-induced apoptosis through secretion of B-cell activating factor and activation of the canonical and non-canonical nuclear factor B pathways

“…30 Based on this study and other reports that the stromal cell-derived chemokines CXCL12 (SDF-1) and CXCL13 induce chemotaxis in MCL, 31,32 we hypothesized that BAFF may also enhance CXCL12 and CXCL13 chemotaxis of primary MCL cells. Using the chemotaxis assay, we compared MCL cell migration responses to CXCL12 and CXCL13 following incubation with medium only, BAFF or BAFF plus BAFFR-Fc.…”

Adipose tissue B2 cells promote insulin resistance through leukotriene LTB4/LTB4R1 signaling

“…Given the robust expression of LTB4R1 on recruited B2 cells, we next examined whether the LTB4/LTB4R1 axis plays a role in B2 cell chemotaxis. In in vitro Transwell chemotaxis assays (34,37), LTB4 led to a dose-responsive increase in splenic B2 cell migration (Figure 2A), and these effects were absent using splenic B2 cells isolated from Ltb4r1 knockout (hereafter referred to as Ltb4r1KO) mice. In addition, cotreatment with the LTB4R1 inhibitor (CP-105696) completely blocked LTB4-induced B2 cell chemotaxis ( Figure 2B).…”

“…In vitro chemotaxis assay. In vitro chemotaxis assays were performed as previously described (34,37). Briefly, ATB2 cells isolated from either HFD-fed WT or Ltb4r1KO mice were placed in the upper chamber of a 5-μm polycarbonate filter, and RPMI with or without LTB4 (Cayman Chemical) was placed in the lower chamber.…”