Role of cAMP in regulating cytotoxic T lymphocyte adhesion and motility.
We investigated the functional role of the cAMP pathway in human cytotoxic T lymphocyte (CTL)-target interaction. Pharmacological increase of intracellular cAMP concentration ([cAMP]i) inhibits killing, especially at low effector-to-target ratios, suggesting an inhibitory effect on CTL recycling. We show that this inhibitory effect is primarily at the level of conjugate formation. Pharmacological increase in [cAMP]i, as well as treatment with cytochalasin D, results in a "rounding up" of the CTL and inhibition of the dramatic changes in shape that occur when a CTL forms a conjugate, even with an irrelevant target. In addition, pharmacological increase in [cAMP]i affects the cytoskeleton of the CTL since it induces a decrease of filamentous actin, as detected by flow cytometry on phalloidin-stained CTL, and a stabilization of microtubules, as detected by increased resistance to the disrupting action of nocodazole. In mature CTL (but not in their immature precursors), T cell receptor triggering by specific targets results in a measurable increase in cAMP levels and strongly synergizes with adenylyl cyclase activators such as prostaglandin E2, cholera toxin and forskolin. We suggest that T cell receptor triggering may induce accumulation of cAMP that interferes with cytoskeleton function and, thus, terminates CTL secretion and adhesion. These effects of cAMP are rapidly reversible and may regulate CTL recycling.
Basel Institute for Immunology, Switzerland.
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Valitutti
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Dessing
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Lanzavecchia
D000199:Actins / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D015232:Dinoprostone / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D008870:Microtubules / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000187:drug effects
D000199:Actins; D005576:Colforsin; D002772:Cholera Toxin; D000242:Cyclic AMP; D015232:Dinoprostone; D002118:Calcium