Cao Qi, Wang Li, Du Fang, Sheng Huiming, Zhang Yan, Wu Juanjuan, Shen Baihua, Shen Tianwei, Zhang Jingwu, Li Dangsheng, Li Ningli
Department of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Res. 2007 Jul;17(7):627-37. doi: 10.1038/cr.2007.46.
Regulatory T cells (Treg) play important roles in immune system homeostasis, and may also be involved in tumor immunotolerance by suppressing Th1 immune response which is involved in anti-tumor immunity. We have previously reported that immunization with attenuated activated autologous T cells leads to enhanced anti-tumor immunity and upregulated Th1 responses in vivo. However, the underlying molecular mechanisms are not well understood. Here we show that Treg function was significantly downregulated in mice that received immunization of attenuated activated autologous T cells. We found that Foxp3 expression decreased in CD4+CD25+ T cells from the immunized mice. Moreover, CD4+CD25+Foxp3+ Treg obtained from immunized mice exhibited diminished immunosuppression ability compared to those from naïve mice. Further analysis showed that the serum of immunized mice contains a high level of anti-CD25 antibody (about 30 ng/ml, p<0.01 vs controls). Consistent with a role of anti-CD25 response in the downregulation of Treg, adoptive transfer of serum from immunized mice to naïve mice led to a significant decrease in Treg population and function in recipient mice. The triggering of anti-CD25 response in immunized mice can be explained by the fact that CD25 was induced to a high level in the ConA activated autologous T cells used for immunization. Our results demonstrate for the first time that immunization with attenuated activated autologous T cells evokes anti-CD25 antibody production, which leads to impeded CD4+CD25+Foxp3+ Treg expansion and function in vivo. We suggest that dampened Treg function likely contributes to enhanced Th1 response in immunized mice and is at least part of the mechanism underlying the boosted anti-tumor immunity.
调节性T细胞（Treg）在免疫系统稳态中发挥重要作用，并且可能通过抑制参与抗肿瘤免疫的Th1免疫反应而参与肿瘤免疫耐受。我们之前报道过，用减毒活化的自体T细胞进行免疫会导致体内抗肿瘤免疫力增强以及Th1反应上调。然而，其潜在的分子机制尚未完全清楚。在此我们表明，在接受减毒活化自体T细胞免疫的小鼠中，Treg功能显著下调。我们发现，免疫小鼠的CD4+CD25+ T细胞中Foxp3表达降低。此外，与未免疫小鼠的CD4+CD25+Foxp3+ Treg相比，免疫小鼠的此类细胞表现出免疫抑制能力减弱。进一步分析表明，免疫小鼠的血清中含有高水平的抗CD25抗体（约30 ng/ml，与对照组相比p<0.01）。与抗CD25反应在Treg下调中的作用一致，将免疫小鼠的血清过继转移至未免疫小鼠会导致受体小鼠中Treg群体和功能显著降低。免疫小鼠中抗CD25反应的触发可以通过以下事实来解释，即用于免疫的伴刀豆球蛋白A活化的自体T细胞中CD25被诱导至高水平。我们的结果首次证明，用减毒活化的自体T细胞进行免疫会引发抗CD25抗体产生，这导致体内CD4+CD25+Foxp3+ Treg扩增和功能受到阻碍。我们认为，Treg功能减弱可能有助于免疫小鼠中Th1反应增强，并且至少是增强的抗肿瘤免疫的部分潜在机制。
