Cholera toxin partially inhibits the T-cell response to phytohaemagglutinin through the ADP-ribosylation of a 45 kDa membrane protein.
This study examines the influence of cholera toxin (CT) on T lymphocyte activation by the mitogenic lectin phytohaemagglutinin (PHA). CT suppressed lectin-induced [3H]thymidine uptake in a dose-dependent fashion and acted synergistically with PHA in the generation of intracellular cyclic AMP. The toxin was assumed to act on Gs, because it also stimulated ADP-ribosylation of a 45 kDa membrane protein in vitro; no additional substrates were seen. The inhibitory effect of the adenylate cyclase/cyclic AMP pathway was shown to be directed at a concomitant stimulatory pathway, namely inositol phospholipid turnover. Lectin-stimulated 32P incorporation into both phosphatidylinositol as well as its 4,5-biphosphate derivative was depressed in the presence of CT or exogenous dibutyryl cyclic AMP. This, in turn, was associated with reduced activation of C-kinase as determined by decreased lectin-induced translocation from the cytosol to the surface membrane. These results indicate that Gs probably acts as a transducer between the PHA receptor and adenylate cyclase and may give rise to an exaggerated adenylate cyclase response in the presence of CT. It would seem as if reduction in inositol phospholipid turnover is related to the elevation of cyclic AMP rather than a CT effect on a putative transducer which acts directly on phospholipase C. Our study does not exclude the existence of non-CT-sensitive transducers in this capacity.
Nel
A E
AE
Department of Internal Medicine, Stellenbosch Medical School, Tygerberg, Republic of South Africa.
Vandenplas
M
M
Wooten
M M
MM
Cooper
R
R
Vandenplas
S
S
Rheeder
A
A
Daniels
J
J
D000244:Adenosine Diphosphate / Q000378:metabolism*; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000378:metabolism; D010835:Phytohemagglutinins; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D013936:Thymidine / Q000493:pharmacokinetics; D013997:Time Factors
D008565:Membrane Proteins; D010712:Phosphatidic Acids; D010835:Phytohemagglutinins; D000244:Adenosine Diphosphate; D003994:Bucladesine; D002772:Cholera Toxin; D000242:Cyclic AMP; D013936:Thymidine