Effect of bacterial toxins on human B cell activation I. Mitogenic activity of pertussis toxin

Abstract

Pertussis toxin (PT) was found to elicit an increased thymidine uptake in resting B lymphocytes purified from human peripheral blood. A significant mitogenic effect was detected for toxin concentrations greater than 100 ng/ml (1nM) and a plateau of stimulation was reached at 1000 ng/ml (10 nM). B cell blasts, activated by a first signal such as Staphylococcus aureus Cowan I or insolubilized anti-mu chain antibody, were also stimulated to DNA synthesis by PT in the same range of concentrations. At lower sub-mitogenic concentrations, the toxin potentiated the response to the low-molecular weight B cell growth factor (LMW-BCGF or 12-kDa BCGF), a progression factor for activated B cells. The "A" or catalytic subunit was devoid of any activity on B cells, suggesting the stimulatory effect of the toxin might be associated with the binding or "B" subunit, as it has been shown for T cells. This hypothesis was strengthened by the observation that, as in T cell, the whole toxin but not the "A" promoter, was able to induce calcium influx in these cells. In addition, the purified "B" oligomer alone was found to promote DNA synthesis in B cells. Finally, a fragment of the soluble cleaved form of the CD23 molecule (Fc epsilon RII) could be involved in the process of PT mitogenicity for B cells.

Pertussis Toxin (PTX) B Subunit and the Nontoxic PTX Mutant PT9K/129G Inhibit Tat-Induced TGF-β Production by NK Cells and TGF-β-Mediated NK Cell Apoptosis

“…However, it is now accepted that PTX-B alone can trigger signal transduction in monocytes, T and B lymphocytes, via a 43-kDa receptor and via either the CD11a/CD18 integrin or the CD14 molecule, leading to cell activation (35,37,49,50). Although it is not yet clear whether this interaction is integrin-mediated in NK cells, we found that PTX-B prevents the synthesis and secretion of TGF-␤ induced by HIV-1 Tat in NK cells, mainly up-regulating Akt phosphorylation via PI3K activation and thus interfering with the ERK/AP-1 signal transduction pathway activated by Tat (19 -24).…”

“…Although it is not yet clear whether this interaction is integrin-mediated in NK cells, we found that PTX-B prevents the synthesis and secretion of TGF-␤ induced by HIV-1 Tat in NK cells, mainly up-regulating Akt phosphorylation via PI3K activation and thus interfering with the ERK/AP-1 signal transduction pathway activated by Tat (19 -24). In this regard, the mechanism of action of PTX-B would be independent of the ADPribosylation of G i -like proteins, which is selectively due to the PTX-A subunit (48,50), but would be related to the ability of PTX-B to activate the PI3K/Akt pathway (37). Indeed, both PTX-B and the PTX mutant, PT9K/129G, lead to PI3K-dependent phosphorylation of Akt, which, in turn, prevents activation of the AP-1 components c-Jun, c-Fos, and JunD induced by Tat in NK cells.…”

Inhibition of intra‐ and extra‐cellular Tat function and HIV expression by pertussis toxin B‐oligomer

“…Several biological effects originally ascribed to the holotoxin have been reproduced by PTX-B, such as mitogenesis in B [16] and T [17] lymphocytes, and potentiation of Th1-and Th2-dependent immune responses [18,19]. Therefore, PTX-B has been developed as an acellular vaccine for B. pertussis infection and as an adjuvant in anti-influenza vaccine [18].…”

The Binding Subunit of Pertussis Toxin Inhibits HIV Replication in Human Macrophages and Virus Expression in Chronically Infected Promonocytic U1 Cells

“…However, it is now clear that PTX-B alone initiates signal transduction (2-5) via a 43-kDa receptor in T lymphocytes (6) and via either the CD11b/CD18 integrin (7,8) or CD14 (9) in myelomonocytic cells. Functionally, PTX-B has been shown to induce multiple effects including DNA synthesis in B cells (10), proliferation of T lymphocytes (11), potentiation of Th1-dependent immune responses via up-regulation of IFN-␥ and IL-2 (4,12), and inhibition of IL-1-induced IL-2 expression and prostaglandin production (13). In fact, many of the effects originally ascribed to PTX have been later reproduced with PTX-B (1,4,14).…”