Subramanyam M, Gutheil W G, Bachovchin W W, Huber B T
Department of Pathology, Tufts University School of Medicine, Boston, MA 02111.
J Immunol. 1993 Mar 15;150(6):2544-53.
HIV-1 Tat has been shown to have an inhibitory effect on the Ag-specific responsiveness of human peripheral T cells. We have previously demonstrated that this retroviral protein binds to and partially inhibits the enzymatic activity of dipeptidyl aminopeptidase type IV (DP IV), also known as CD26, which is expressed on a variety of mammalian tissue, including T lymphocytes. A number of studies have implicated a role for DP IV in the activation of T lymphocytes. By utilizing HIV-1 Tat, as well as ProboroPro, a potent and specific boronic acid analog inhibitor of DP IV, we show here that blocking DP IV partially inactivates Ag and anti-CD3-mediated T cell proliferation. Neither mitogen nor anti-CD2 mediated proliferation of T lymphocytes, however, is impaired by blocking DP IV. The target molecule for the inhibition induced by both compounds was confirmed by the finding that soluble DP IV neutralized the reduced Ag responsiveness. The Ag-specific inhibition could be overcome by the addition of exogenous IL-2, suggesting that blocking or inactivation of DP IV results in a state of anergy, probably by interfering with the delivery or amplification of a signal necessary for IL-2 production. This is further substantiated by the finding that costimulation of human PBMC via the CD28 molecule, which initiates a non-TCR-dependent signaling pathway, overcomes the reduced Ag responsiveness induced by Tat and ProboroPro. The fact that ProboroPro has no impact on stimulation of T cells with PMA and ionomycin implies that blocking DP IV is influencing events before the activation of protein kinase C and Ca2+ flux. These results suggest that DP IV is necessary for amplification of signals generated by the engagement of the TCR-CD3 complex by nominal Ag.
已证明HIV-1反式激活因子（Tat）对人外周血T细胞的抗原特异性反应性具有抑制作用。我们之前已证明，这种逆转录病毒蛋白可与二肽基氨基肽酶IV（DP IV，也称为CD26）结合并部分抑制其酶活性，CD26在包括T淋巴细胞在内的多种哺乳动物组织中表达。多项研究表明DP IV在T淋巴细胞激活中起作用。通过利用HIV-1 Tat以及ProboroPro（一种强效且特异性的DP IV硼酸类似物抑制剂），我们在此表明，部分阻断DP IV会使抗原和抗CD3介导的T细胞增殖部分失活。然而，阻断DP IV并不会损害丝裂原或抗CD2介导的T淋巴细胞增殖。两种化合物诱导的抑制作用的靶分子通过以下发现得以证实：可溶性DP IV可中和降低的抗原反应性。添加外源性白细胞介素-2（IL-2）可克服抗原特异性抑制作用，这表明阻断或使DP IV失活可能通过干扰IL-2产生所需信号的传递或放大而导致无反应状态。通过CD28分子对人外周血单核细胞（PBMC）进行共刺激可启动非T细胞受体（TCR）依赖性信号通路，这一发现进一步证实了上述观点，即共刺激可克服由Tat和ProboroPro诱导的降低的抗原反应性。ProboroPro对佛波酯（PMA）和离子霉素刺激T细胞无影响这一事实表明，阻断DP IV正在影响蛋白激酶C激活和钙离子通量之前的事件。这些结果表明，DP IV对于由名义抗原与TCR-CD3复合物结合产生的信号放大是必需的。
