The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation.
The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation.
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吲哚胺2,3-二加氧酶途径对于人浆细胞类动物树突状细胞诱导的适应性T调节细胞的产生至关重要。
DOI：
10.4049/jimmunol.181.8.5396
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发表时间：
2008-10-15
期刊：
影响因子：
--
通讯作者：
Blazar BR
中科院分区：
文献类型：
--
作者：
Chen W;Liang X;Peterson AJ;Munn DH;Blazar BR
人浆细胞样树突状细胞（PDCs）可以驱动幼稚的同种异体CD 4 + CD 25 − T细胞分化为CD 4 + CD 25 + Foxp 3+调节性T细胞（Tcells）。然而，PDC诱导的Treg产生的细胞内机制尚不清楚。在这里，我们发现人PDCs表达高水平的吲哚胺2，3-双加氧酶（IDO），一种分解代谢色氨酸降解的细胞内酶。用CpG寡脱氧核苷酸触发Toll样受体9激活PDCs以上调B7配体和HLA-DR抗原的表面表达，但也显著增加IDO的表达，并导致从具有有效抑制细胞功能的CD 4 + CD 25 − T细胞产生诱导型Tcl 3。用药理学抑制剂1-甲基-D-色氨酸（1 MT）阻断IDO活性显著消除了PDC驱动的诱导型Treg生成和抑制细胞功能。添加色氨酸的直接下游代谢物犬尿氨酸（KYN）绕过1 MT效应，并恢复PDC驱动的Treg生成。我们的研究结果表明，IDO途径对于从CD 4 + CD 25 − T细胞产生PDC驱动的Treg是必不可少的，并且暗示KYN途径代谢物的产生是该过程的关键介导剂。
Human plasmacytoid dendritic cells (PDCs) can drive naïve, allogeneic CD4+CD25− T cells to differentiate into CD4+CD25+Foxp3+ regulatory T cells (Tregs). However, the intracellular mechanism(s) underlying PDC-induced Treg generation is unknown. Here we show human PDCs express high levels of indoleamine 2,3-dioxygenase (IDO), an intracellular enzyme that catabolizes tryptophan degradation. Triggering of Toll-like receptor 9 with CpG oligodeoxynucleotides activates PDCs to upregulate surface expression of B7 ligands and HLA-DR antigen, but also significantly increases the expression of IDO, and results in the generation of inducible Tregs from CD4+CD25− T cells with potent suppressor cell function. Blocking IDO activity with a pharmacologic inhibitor 1-methyl-D-tryptophan (1MT) significantly abrogates PDC-driven inducible Treg generation and suppressor cell function. Adding kynurenine (KYN), the immediate downstream metabolite of tryptophan, bypasses the 1MT effect, and restores PDC-driven Treg generation. Our results demonstrate that IDO pathway is essential for PDC-driven Treg generation from CD4+CD25− T cells, and implicates the generation of KYN-pathway metabolites as the critical ediator of this process.
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影响因子：
30.5
作者：
Fallarino, F;Grohmann, U;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
4.4
作者：
Fallarino, F;Orabona, C;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
30.5
作者：
Grohmann, U;Orabona, C;Puccetti, P
通讯作者：
Puccetti, P
影响因子：
4.4
作者：
Hwu, P;Du, MX;Young, HA
通讯作者：
Young, HA
影响因子：
6.4
作者：
Bilsborough, J;George, TC;Viney, JL
通讯作者：
Viney, JL