Bartik M M, Bauman G P, Brooks W H, Roszman T L
Department of Microbiology and Immunology, College of Medicine, University of Kentucky, Lexington 40536.
Cell Immunol. 1994 Oct 1;158(1):116-30. doi: 10.1006/cimm.1994.1261.
Stimulation of highly purified human T cells with immobilized anti-CD3 monoclonal antibody (mAb) in the presence of cAMP-inducing agents results in inhibition of proliferation by these T cells. In the present study, experiments were performed to determine how costimulatory signals modulate the inhibitory effects of cAMP-elevating agents on proliferation and interleukin 2 (IL-2) secretion by anti-CD3 mAb-stimulated T cells. Accordingly, the level of anti-CD3 mAb-induced T cell proliferation was determined in the presence or absence of accessory cells, anti-CD28 mAb, or phorbol myristic acid (PMA) in the presence of the adenylyl cyclase (AC)-linked receptor agonists prostaglandin E2 (PGE2), or isoproterenol (ISO) as well as the AC activator forskolin (FSK) or the cAMP analog dibutyryl-cAMP (dB-cAMP). While all three costimulators enhanced the level of anti-CD3 mAb-induced T cell proliferation and IL-2 secretion, they were variable in their ability to overcome the immunosuppressive effects of the cAMP elevating agents. The order of potency of the costimulatory signals in reversing the inhibitory effects of cAMP-elevating agents on anti-CD3 mAb-induced T cell proliferation and IL-2 secretion was PMA > accessory cells > anti-CD28 mAb. Differences were noted in the ability of the costimulatory signals to overcome the immunosuppressive effects of the various cAMP-inducing agents. Thus, the effects of PGE2 or ISO on T cell proliferation or IL-2 secretion were more readily overcome by costimulatory signals than those elicited by FSK or dB-cAMP. Experiments designed to investigate the mechanisms involved in these effects showed that neither accessory cells nor anti-CD28 mAb altered the level of cAMP accumulation or protein kinase A (PKA) activity in T cells stimulated with cAMP-elevating agents. However, PMA was found to decrease both cAMP accumulation and PKA activity in T cells stimulated with PGE2 or ISO but not FSK. These results suggest that the overall immunosuppressive effects of naturally occurring substances such as PGE2 or catecholamines may be altered by costimulatory signals when antigen-specific T cells interact with antigen-presenting cells.
在环磷酸腺苷（cAMP）诱导剂存在的情况下，用固定化抗CD3单克隆抗体（mAb）刺激高度纯化的人T细胞，会导致这些T细胞的增殖受到抑制。在本研究中，进行了实验以确定共刺激信号如何调节cAMP升高剂对抗CD3 mAb刺激的T细胞增殖和白细胞介素2（IL-2）分泌的抑制作用。因此，在存在或不存在辅助细胞、抗CD28 mAb或佛波醇肉豆蔻酸酯（PMA）的情况下，在腺苷酸环化酶（AC）连接受体激动剂前列腺素E2（PGE2）或异丙肾上腺素（ISO）以及AC激活剂福斯高林（FSK）或cAMP类似物二丁酰-cAMP（dB-cAMP）存在的情况下，测定抗CD3 mAb诱导的T细胞增殖水平。虽然所有三种共刺激剂都增强了抗CD3 mAb诱导的T细胞增殖水平和IL-2分泌，但它们克服cAMP升高剂免疫抑制作用的能力各不相同。共刺激信号逆转cAMP升高剂对抗CD3 mAb诱导的T细胞增殖和IL-2分泌抑制作用的效力顺序为PMA>辅助细胞>抗CD28 mAb。注意到共刺激信号克服各种cAMP诱导剂免疫抑制作用的能力存在差异。因此，与FSK或dB-cAMP相比，共刺激信号更容易克服PGE2或ISO对T细胞增殖或IL-2分泌的影响。旨在研究这些效应所涉及机制的实验表明，辅助细胞和抗CD28 mAb均未改变用cAMP升高剂刺激的T细胞中cAMP积累水平或蛋白激酶A（PKA）活性。然而，发现PMA可降低用PGE2或ISO而非FSK刺激的T细胞中的cAMP积累和PKA活性。这些结果表明，当抗原特异性T细胞与抗原呈递细胞相互作用时，天然存在的物质如PGE2或儿茶酚胺的整体免疫抑制作用可能会被共刺激信号改变。
