Pertussis toxin triggers rapid second messenger production in human T lymphocytes.
Pertussis toxin (PT) is a known mitogen for T lymphocytes. The mechanism by which the toxin stimulates proliferation has remained obscure and paradoxical because, in some types of cells, the toxin also inhibits growth factor-mediated signal transduction. It has previously been shown that the adenosine-diphosphate ribosyltransferase activity of the toxin is not required to produce the mitogenic effect. A biochemical explanation for the mitogenic activity has therefore remained obscure. We investigated the biochemical basis for the mitogenic activity of PT by using the transformed human T cell line, Jurkat. PT stimulated a rapid rise in cytosolic-free [Ca2+] from both intra- and extracellular sources. This was associated with an increase in the cellular diacylglycerol and inositol triphosphate levels with a concomitant decrease in the levels of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate. The half-maximal effective dose of PT was 1.7 nM. PT also stimulated the production of interleukin 2. Only the holotoxin or B-oligomer (the presumptive membrane-binding subunit) was capable of stimulating an increase in [Ca2+] in these cells. This activity of PT mimicked that of some anti-T3-T cell antigen receptor complex monoclonal antibodies that also stimulate increases in the second messengers, diacylglycerol and Ca2+. The effects of PT and anti-T3 complex antibody were identical and not additive in Jurkat cells, suggesting that both agents were activating the same signal transduction pathway. These data provide a mechanistic explanation for the mitogenic effects of PT and suggest that the toxin may be interacting with a specific receptor in the T lymphocyte plasma membrane.
D000954:Antigens, Surface / Q000378:metabolism; D017252:CD3 Complex; D002118:Calcium / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002461:Cell Line, Transformed; D004075:Diglycerides / Q000096:biosynthesis; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D037342:Pertussis Toxin; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D000954:Antigens, Surface; D017252:CD3 Complex; D004075:Diglycerides; D007295:Inositol Phosphates; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D002118:Calcium