Distinct Role of CD80 and CD86 in the Regulation of the Activation of B Cell and B Cell Lymphoma

Abstract

To date, not much has been known regarding the role of CD80 and CD86 molecules in signaling of B cells. The CD28/CTLA4 ligands, CD80 (B7-1) and CD86 (B7-2), are expressed on the surface of freshly isolated splenic B cells, and their expression is up-regulated by lipopolysaccharides. In the present study, we have investigated whether signaling via CD80/CD86 could alter the proliferation and immunoglobulin synthesis of B cells. Splenic B cells were stimulated with lipopolysaccharides in the presence of anti-B7-1 (16-10A1) and anti-B7-2 (GL1) monoclonal antibodies (mAbs). Exciting features observed during the study were that cross-linking of CD86 with GL1 enhanced the proliferation and production of IgG1 and IgG2a isotypes. In contrast, anti-B7-1 (16-10A1) mAb could efficiently block the proliferation and production of IgG1 and IgG2a. Furthermore, GL1 mAb could also induce the secretion of IgG isotypes from B cell lymphomas. Importantly, 16-10A1 could retard the growth of lymphomas and favored the up-regulation of pro-apoptotic molecules caspase-3, caspase-8, Fas, FasL, Bak, and Bax and down-regulation of antiapoptotic molecule Bcl-x(L). In contrast, GL1 augmented the level of anti-apoptotic molecules Bcl-w and Bcl-x(L) and decreased the levels of pro-apoptotic molecule caspase-8, thereby providing a novel insight into the mechanism whereby triggering through CD80 and CD86 could deliver regulatory signals. Thus, this study is the first demonstration of a distinct signaling event induced by CD80 and CD86 molecules in B cell lymphoma. Finally, the significance of the finding is that CD80 provided negative signal for the proliferation and IgG secretion of normal B cells and B cell lymphomas. In contrast, CD86 encouraged the activity of B cells.Evidence from a variety of studies has suggested that the B cell contact with T helper cells is important for its optimal activation and responsiveness to cytokines during Ig secretion (1-3). Contact between B and T cells can be mediated by antigen presentation, as well as antigen-independent cell interaction by molecules known as adhesion (LFA-1, LFA-3, ICAM-1, etc.) and costimulatory molecules (CD80, CD86, CD40, etc.) (3-7). Signals from T cells induce two opposite fates in B cells: clonal expansion of B cells that bind specifically to foreign antigens and clonal deletion of equivalent B cells that bind self-antigen. The role of costimulatory molecules is very well established in the activation of T cells (3), but nothing has been determined definitively about how these molecules operate in the activation and differentiation of B cells (8 -10).The best defined co-stimulators to date are two structurally related proteins, . Both of these play a major role in providing costimulation to T cells, leading to their proliferation, cytokine production, and development of effector functions. CD80 and CD86 could also serve as counter-receptors that transduce distinct signal to the antigen-presenting cells upon engagement by CD28 or CTLA-4. The intracellular domains of CD80 and CD86 are ...

Selective Regulation of Mature IgG1 Transcription by CD86 and β2-Adrenergic Receptor Stimulation

“…Previous data also indicated that the amount of IgG1 protein produced by CD40L/IL-4-activated B cells is increased further when CD86 (16,26) and/or ␤ 2 AR (16) are costimulated on the B cell. However, the mechanism responsible for mediating the latter enhancing effect was unknown.…”

“…Although these findings were attributed to a lack of CD28 costimulation on the Th2 cell that resulted in a decrease in the level of IL-4 and CD40L costimulation provided to the B cell, these findings also suggested that CD86 costimulation might generate a signal within the B cell to regulate the level of a Th celldependent Ab response. Recent in vitro data show that the stimulation of CD86 on a B cell activated through CD40 and the IL-4R with or without BCR stimulation increases the level of IgG1 and IgE produced (16,25) and differentially affects the level of antiapoptotic and proapoptotic molecules expressed (26). Likewise, both host and donor B cells from chimeric mice that received donor cells from CD80/CD86-deficient mice and were challenged with a protein Ag were able to produce Ag-specific IgG1, but the level of IgG1 produced by the CD80/CD86-deficient cells was decreased compared with that of the host B cells (27).…”

Cell‐extrinsic CTLA4‐mediated regulation of dendritic cell maturation depends on STAT3

“…Several studies have shown the importance of reverse signaling through B7 molecules in various immune cells [39][40][41]. Nevertheless, the molecules involved and consequences of reverse signaling remain elusive.…”

“…The fact that plate-bound CTLA4Fc alone could mimic iTreg cell function in controlling DC maturation cannot be reconciled by these models. Therefore, we propose that a cell-extrinsic model of CTLA4 function operates not only by the direct removal of costimulatory molecule from APCs, which requires persistent T cell-DC interaction, but also via triggering reverse signaling in CD80/CD86-expressing DCs.Several studies have shown the importance of reverse signaling through B7 molecules in various immune cells [39][40][41]. Nevertheless, the molecules involved and consequences of reverse signaling remain elusive.…”

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

“…6,38,39 Our data are important because they emphasize that co-stimulatory molecules play a pivotal role in APC-mediated immune responses, particularly T-cell activation and proliferation. [40][41][42][43][44][45] In the study herein, we demonstrate the ability of autologous exosomes to be taken up by peripheral monocytes and DCs. Further, they have the potential to modulate the expression of co-stimulatory molecules on APCs from patients with PBC.…”