Modulation of B‐cell activation by the B subunit of Escherichia coli enterotoxin: receptor interaction up‐regulates MHC class II, B7, CD40, CD25 and ICAM‐1

Abstract

SUMMARYThe B subunits of cholera toxin (CtxB) and Escherichia coli heat-labile enterotoxin ( EtxB) are non-toxic lectins that bind and cross-link a ubiquitous cell glycolipid receptor, ganglioside GM1, and are recognized as potent mucosal and systemic immunogens. Here we examine the role of EtxB receptor occupancy in modulating the activation of B cells, in vitro, in primary lymphocyte cultures containing B and T cells. When 48-hr spleen cell cultures containing EtxB were compared with those in the presence of a non-receptor binding mutant, EtxB(G33D), a marked shift in the ratio of CD4+ T cells5B cells was noted. Evidence suggested that this was the result of either enhanced survival or proliferation of B cells associated with receptor occupancy by EtxB. Investigation revealed that EtxB induced only a minimal increase in proliferation above that of EtxB(G33D), in mixed cell cultures, and failed to induce any cell division of purified B cells or T cells. In contrast, receptor-binding by EtxB markedly up-regulated the expression of major histocompatability complex (MHC ) class II, B7, intracellular adhesion molecule-1 (ICAM-1), CD40 and CD25 on the B-cell surface. These results indicate that the polyclonal eÂects of EtxB on B cells are not associated with wide-scale proliferation, but more likely with maintenance of B-cell survival by activation of molecules essential for B-cell diÂerentiation. The findings also highlight the essential role of GM1-interaction with EtxB in the regulation of lymphocyte responses.

Mutants of Type II Heat-Labile Enterotoxin LT-IIa with Altered Ganglioside-Binding Activities and Diminished Toxicity Are Potent Mucosal Adjuvants

“…Binding of CT, LT-I, and LT-IIa, but not binding of LT-IIb, to CD8 ϩ T cells induces apoptosis (2,58). Binding of CT or LT-I to B cells leads to polyclonal activation and to upregulated expression of MHC-II, B7, CD40, CD80, CD86, ICAM-1, and IL-2R␣ (2,36,41). Type I enterotoxins also upregulate expression of CD80 and CD86 on macrophages and dendritic cells (36).…”

“…Full activation of antigen-specific T cells requires interaction between the T-cell receptor and MHC-II, as well as interaction between CD28 and B7 and/or between CD40 and CD40L on the surfaces of T cells and antigen-presenting cells (APC) (30). Since it was previously reported that CT, LT-I, LT-IIa, and LT-IIb modulate the expression of MHC-II and costimulatory molecules (CD40, CD80, and CD86) on the surface of APC (2,33,36,41), the effects of the mutant enterotoxins LT-IIa(T14S), LT-IIa(T14I), and LT-IIa(T14D) on the levels of expression of CD40, CD80 (B7-1), CD86 (B7-2), and MHC-II on the surfaces of resting B cells (B220 ϩ ) and dendritic cells (CD11c ϩ ) isolated from the spleens of naïve mice were examined.…”

Cholera Toxin B-Subunit Prevents Activation and Proliferation of Human CD4+ T Cells by Activation of a Neutral Sphingomyelinase in Lipid Rafts

“…CTB triggers the polyclonal activation of B cells. This activation occurs in the absence of significant proliferation and involves the up-regulation of a number of important molecules, namely MHC class II (Ia), B7, CD40, ICAM-1, and IL-2R␣ (CD25) (1,2). CTB induces selective apoptosis of T CD8 ϩ cells.…”

Cholera Toxin B Pretreatment of Macrophages and Monocytes Diminishes Their Proinflammatory Responsiveness to Lipopolysaccharide

“…This effect may be due to the activating effect of CTB on B cells, including the up-regulation of MHC class II molecules (12,13). Also involved may be the induction of apoptosis in CD8…”