Modulation of T cell proliferation by stimulation of the beta-adrenergic receptor: lack of correlation between inhibition of T cell proliferation and cAMP accumulation.
The presence of beta-adrenergic receptors on T cells suggests the potential for modulating T cell function upon binding of an appropriate agonist. Utilizing highly purified human T cells we assessed the proliferative capacity of T cells upon stimulation with immobilized anti-CD3 monoclonal antibody (mAb) in the presence of the beta-adrenergic agonist isoproterenol (ISO). The proliferative response of T cells and their CD4+, CD8+, or CD45RO+ subsets to anti-CD3 mAb was inhibited in a dose-dependent manner by ISO. In parallel experiments, various concentrations of prostaglandin E2 (PGE2) were added to anti-CD3 mAb-stimulated T cells and their subsets. Similar dose-dependent effects were observed with the important exception that PGE2 was considerably more immunosuppressive than ISO. The results also showed that PGE2 was a much more effective inhibitor of anti-CD3 mAb-induced interleukin 2 synthesis by T cells than was ISO. Because both the beta-adrenergic and PGE2 receptors are linked to adenylyl cyclase, the magnitude and kinetics of cAMP accumulation in T cells and their subsets were determined after stimulation with ISO or PGE2. The results show that PGE2 induced a greater and more sustained accumulation of cAMP than ISO. Moreover, these differences could not be ascribed to differential modulation of cAMP phosphodiesterase activity. Correlation of the degree of inhibition of anti-CD3 mAb-induced T cell proliferation by PGE2 or ISO with the level of accumulation of cAMP in these stimulated T cells indicate that, on an equimolar basis, cAMP elicited by PGE2 is more immunosuppressive than that induced by ISO. These results suggest that qualitative differences in cAMP accumulation in T cells have an important role in the subsequent modulation of anti-CD3 mAb-induced T cell proliferation.
Department of Microbiology and Immunology, University of Kentucky Medical Center, Lexington 40536-0084.
M M
MM
Bartik
W H
WH
Brooks
T L
TL
Roszman
D017252:CD3 Complex / Q000276:immunology; D000242:Cyclic AMP / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000096:biosynthesis; D007545:Isoproterenol / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000502:physiology*
D017252:CD3 Complex; D007376:Interleukin-2; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D015232:Dinoprostone; D007545:Isoproterenol