COSTIMULATORY SIGNALS MODULATE THE ANTIPROLIFERATIVE EFFECTS OF AGENTS THAT ELEVATE CAMP IN T-CELLS

Stimulation of highly purified human T cells with immobilized anti-CD3 monoclonal antibody (mAb) in the presence of cAMP-inducing agents res ults in inhibition of proliferation by these T cells. In the present s tudy, experiments were performed to determine how costimulatory signal s modulate the inhibitory effects of cAMP-elevating agents on prolifer ation and interleukin 2 (IL-2) secretion by anti-CD3 mAb-stimulated T cells. Accordingly, the level of anti-CD3 mAb-induced T cell prolifera tion was determined in the presence or absence of accessory cells, ant i-CD28 mAb, or phorbol myristic acid (PMA) in the presence of the aden ylyl cyclase (AC)-linked receptor agonists prostaglandin E(2) (PGE(2)) , or isoproterenol (ISO) as well as the AC activator forskolin (FSK) o r the cAMP analog dibutyryl-cAMP (dB-cAMP). While all three costimulat ors enhanced the level of anti-CD3 mAb-induced T cell proliferation an d IL-2 secretion, they were variable in their ability to overcome the immunosuppressive effects of the cAMP elevating agents. The order of p otency of the costimulatory signals in reversing the inhibitory effect s of cAMP-elevating agents on anti-CD3 mAb-induced T cell proliferatio n and IL-2 secretion was PMA > accessory cells > anti-CD28 mAb. Differ ences were noted in the ability of the costimulatory signals to overco me the immunosuppressive effects of the various cAMP-inducing agents. Thus, the effects of PGE(2) or ISO on T cell proliferation or IL-2 sec retion were more readily overcome by costimulatory signals than those elicited by FSK or dB-cAMP. Experiments designed to investigate the me chanisms involved in these effects showed that neither accessory cells nor anti-CD28 mAb altered the level of cAMP accumulation or protein k inase A (PKA) activity in T cells stimulated with cAMP-elevating agent s. However, PMA was found to decrease both cAMP accumulation and PKA a ctivity in T cells stimulated with PGE(2) or ISO but not FSK. These re sults suggest that the overall immunosuppressive effects of naturally occurring substances such as PGE(2) or catecholamines may be altered b y costimulatory signals when antigen-specific T cells interact with an tigen-presenting cells. (C) 1994 Academic Press, Inc.