Modulation of Regulatory T Cell Function by Monocyte-Derived Dendritic Cells Matured through Electroporation with mRNA Encoding CD40 Ligand, Constitutively Active TLR4, and CD70
Modulation of Regulatory T Cell Function by Monocyte-Derived Dendritic Cells Matured through Electroporation with mRNA Encoding CD40 Ligand, Constitutively Active TLR4, and CD70
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DOI：
10.4049/jimmunol.1201008
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发表时间：
2013-08-15
影响因子：
4.4
通讯作者：
Aerts, Joeri L.
中科院分区：
文献类型：
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作者：
Pen, Joeri J.;De Keersmaecker, Brenda;Aerts, Joeri L.
调节性 T 细胞 (T-regs) 通过多种机制抵消抗癌免疫反应，限制基于树突状细胞 (DC) 的抗癌免疫治疗。在这项研究中，我们研究了各种 DC 激活刺激对 T-reg 功能的影响。我们将电穿孔激活的 DC 与编码组成型活性 TLR4 (caTLR4) 和 CD40 配体 (DiMix-DC) 的 mRNA 或这些因子与编码共刺激分子 CD70 (TriMix-DC) 的 mRNA 一起与在炎症细胞因子混合物存在下成熟的 DC（用细胞因子 IL-1 组合成熟的 DC）进行了比较。 beta、IL-6、TNF-α 和 PGE(2))，因为它们能够在不同水平上抵消 T 调节细胞。我们首先证明，在不同DC成熟刺激的影响下，从CD4(+)CD252(-) T细胞开始的T-reg诱导程度没有差异。其次，我们发现 DiMix- 和 TriMix-DC 都可以部分减轻 CD8+ T 细胞的 T-reg 抑制。第三，我们观察到用 DiMix-DC 或 TriMix-DC 预培养的 CD8(+) T 细胞受到部分保护，免受随后的 T-reg 抑制。最后，我们发现，T-regs 在 TriMix-DCs 存在下共培养，但 DiMix-DCs 没有，部分失去了抑制能力。伴随着 T-reg 上 CD27 和 CD25 表达的减少，以及 T-bet 表达的增加以及 IFN-γ、TNF-α 和 IL-10 的分泌，表明 T-reg 表型向 Th1 表型转变。总之，这些数据表明 TriMix-DC 不仅能够抑制 T-reg 功能，而且在某些情况下能够将 T-reg 重编程为 Th1 细胞。
Regulatory T cells (T-regs) counteract anticancer immune responses through a number of mechanisms, limiting dendritic cell (DC)-based anticancer immunotherapy. In this study, we investigated the influence of various DC activation stimuli on the T-reg functionality. We compared DCs activated by electroporation with mRNA encoding constitutively active TLR4 (caTLR4) and CD40 ligand (DiMix-DCs), or these factors together with mRNA encoding the costimulatory molecule CD70 (TriMix-DCs) with DCs maturated in the presence of a mixture of inflammatory cytokines (DCs maturated with a combination of the cytokines IL-1 beta, IL-6, TNF-alpha, and PGE(2)) for their ability to counteract T-regs on different levels. We first demonstrated that there was no difference in the extent of T-reg induction starting from CD4(+)CD252(-) T cells under the influence of the different DC maturation stimuli. Second, we showed that both DiMix- and TriMix-DCs could partly alleviate T-reg inhibition of CD8(+) T cells. Third, we observed that CD8(+) T cells that had been precultured with DiMix-DCs or TriMix-DCs were partially protected against subsequent T-reg suppression. Finally, we showed that T-regs cocultured in the presence of TriMix-DCs, but not DiMix-DCs, partially lost their suppressive capacity. This was accompanied by a decrease in CD27 and CD25 expression on T-regs, as well as an increase in the expression of T-bet and secretion of IFN-gamma, TNF-alpha, and IL-10, suggesting a shift of the T-reg phenotype toward a Th1 phenotype. In conclusion, these data suggest that TriMix-DCs are not only able to suppress T-reg functions, but moreover could be able to reprogram T-regs to Th1 cells under certain circumstances.