Bacterial toxins affect early events of T lymphocyte activation.

Abstract

The effects of pertussis toxin and cholera toxin on early events of T lymphocyte activation were examined in the T lymphocyte cell line, Jurkat. Pertussis toxin treatment of these T cells increased inositol phosphates production and led to increases in intracellular free calcium concentration. These effects were produced by the isolated B (binding) subunit of pertussis toxin, alone. Inositol phosphates production resulting from perturbation of the T cell antigen receptor-CD3 complex by MAb was not affected by pertussis toxin treatment but was markedly inhibited by cholera toxin. This effect of cholera toxin paralleled elevations in cAMP content. However, forskolin, in concentrations equipotent for cAMP production, was a weaker inhibitor of inositol phosphates production. Cholera toxin inhibition of inositol phosphates production did not result from inhibition of baseline incorporation of inositol into phosphoinositide substrates of phospholipase C. These studies underline the complexity of toxin effects on cellular systems and suggest that other approaches will be required to implicate guanine nucleotide-binding regulatory proteins in control of the early events of T lymphocyte activation. However, the data presented here provide a molecular basis for the clinical observations of lymphocytosis and the in vitro observations of lymphocyte mitogenesis after pertussis toxin stimulation.

Characterization of rabbit ileal receptors for Clostridium difficile toxin A. Evidence for a receptor-coupled G protein.

“…4) that toxin A accelerates the association of 35S-GTP'yS with BB is consistent with this hypothesis, and the modulation of 3H-toxin A binding by guanine nucleotides (Table II) suggests that the toxin A receptor is coupled directly to a G protein. Numerous other bacterial toxins (46,47) and viral proteins (48) have also been found to bind to known physiologic cell surface receptors, or to activate cells by membrane receptor before being internalized and expressing enzymatic activity (49)(50)(51). Although it is possible that these phenomena reflect random association of toxins with any cell surface molecule, it seems more likely that teleologically these microbial proteins are exploiting the normal process ofligand binding followed by internalization to gain access to the interior ofthe cell.…”

Pertussis toxin-induced cytokine differentiation and clonal expansion of T cells is mediated predominantly via costimulation

“…PTX has well established adjuvant properties [7,8]. However, PTX differs from most classical adjuvants by its ability to concomitantly induce Th1 and Th2 cytokine responses [8].…”

“…Recent studies have shown that other microbial products, such as CpGs, Pertussis toxin (PTX) or Cholera toxin, also have adjuvant effects [6][7][8]. Interestingly, PTX has been used for many years to enhance the induction of organ-specific autoimmune diseases elicited by immunization of laboratory animals with the appropriate tissue autoantigens [8,9].…”

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).…”

“…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). Like PTX-B, a genetically modified form of PTX, PT-9K/129G, devoid of the A-protomer-specific enzymatic activity but retaining a functional PTX-B subunit (15)(16)(17)(18), has been successfully used as a mucosal adjuvant for a tetanus vaccine in mice (16), and it is safely administered to humans as a vaccine against Bordetella pertussis infection (17).…”