Vendetti Silvia, Riccomi Antonella, Sacchi Alessandra, Sciaraffia Ester, Gatta Lucia, Pioli Claudio, De Magistris Maria Teresa
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Viale Regina Elena, Rome, Italy.
Immunol Lett. 2008 Jan 15;115(1):59-69. doi: 10.1016/j.imlet.2007.10.003. Epub 2007 Nov 5.
Cholera toxin (CT) is known to inhibit the proliferation of murine and human T lymphocytes. In this study we have analysed the mechanisms underlying the inhibitory effect of CT on subpopulations of human CD4+ and CD8+ T lymphocytes. We show that CT dramatically prevents the activation of resting T lymphocytes, whereas it has a minor effect on cells that have been previously activated. Analysis of DNA content of the CT-treated T cells showed an arrest in the G(0)/G(1) phase and this correlated with high expression of the cyclin-dependent kinase inhibitor p27(kip). Moreover, we show that CT up-regulates the expression of the inhibitory molecule CTLA-4 in naïve, effector and memory resting CD4+ T cells and in resting CD8+ T lymphocytes. The regulation of CTLA-4 expression by CT is at the transcriptional level. Indeed, in cells treated with CT we observed an increase of two mRNA variants coding for the membrane and the soluble CTLA-4 molecules. In parallel with the up-regulation of the inhibitory CTLA-4, CT down-modulates the costimulatory molecule CD28 on CD4+ and CD8+ resting T cells. The increased expression of CTLA-4 played a role in controlling T cell activation and function as blocking anti-CTLA-4 F(ab')(2) mAbs partially inhibited anti-CD3 mAbs induced proliferation. These findings show that the inhibition of T cell proliferation by CT affects early stages of the T cell activation and involves the modulation of costimulatory molecules CTLA-4 and CD28 on resting T cells.
已知霍乱毒素（CT）可抑制小鼠和人类T淋巴细胞的增殖。在本研究中，我们分析了CT对人类CD4+和CD8+ T淋巴细胞亚群产生抑制作用的潜在机制。我们发现，CT能显著阻止静息T淋巴细胞的激活，而对先前已激活的细胞影响较小。对经CT处理的T细胞的DNA含量分析显示，细胞停滞于G(0)/G(1)期，这与细胞周期蛋白依赖性激酶抑制剂p27(kip)的高表达相关。此外，我们发现CT可上调初始、效应和记忆静息CD4+ T细胞以及静息CD8+ T淋巴细胞中抑制性分子CTLA-4的表达。CT对CTLA-4表达的调节作用发生在转录水平。实际上，在用CT处理的细胞中，我们观察到编码膜结合型和可溶性CTLA-4分子的两种mRNA变体的表达增加。与抑制性CTLA-4的上调同时发生的是，CT下调静息CD4+和CD8+ T细胞上的共刺激分子CD28。CTLA-4表达的增加在控制T细胞激活中发挥作用，因为阻断抗CTLA-4 F(ab')(2)单克隆抗体可部分抑制抗CD3单克隆抗体诱导的增殖。这些发现表明，CT对T细胞增殖的抑制作用影响T细胞激活的早期阶段，并且涉及对静息T细胞上共刺激分子CTLA-4和CD28的调节。
