IDO expands human CD4+CD25high regulatory T cells by promoting maturation of LPS-treated dendritic cells
IDO expands human CD4+CD25high regulatory T cells by promoting maturation of LPS-treated dendritic cells
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DOI：
10.1002/eji.200636704
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发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Anegon, Ignacio
中科院分区：
文献类型：
--
作者：
Hill, Marcelo;Tanguy-Royer, Severine;Anegon, Ignacio
我们之前已经证明，人单核细胞来源的树突状细胞（DC）在成熟时表达吲哚胺2,3-双加氧酶（IDO），以及犬尿氨酸途径的其他几种酶的mRNA水平。该途径的耐受性机制尚不清楚。在这里，我们发现lps处理的DC代谢色氨酸和喹啉酸。我们发现IDO有助于LPS和tnf - α + poly（I:C）诱导的DC成熟，因为使用两种不同的抑制剂抑制IDO会损害DC成熟。使用短发夹RNA敲除IDO也导致lps诱导的成熟减少。与这些结果一致，色氨酸衍生的分解产物3-羟基苯甲酸和3-羟基犬尿氨酸增加了lps处理的DC的成熟。关于这一作用的分子机制，IDO在lps诱导的活性氧产生和NF-kappa B活化这两个导致DC成熟的过程中起到了中间通路的作用。最后，我们发现成熟DC以ido依赖的方式扩展CD4(+)CD25（高）调节性T细胞。总之，我们发现IDO在DC成熟过程中构成了一个中间途径，导致CD4(+)CD25（高）调节性T细胞的扩增。
We have previously shown that human monocyte-derived dendritic cells (DC) express indoleamine 2,3-dioxygenase (IDO), as well as several other enzymes of the kynurenine pathway at the mRNA level upon maturation. The tolerogenic mechanisms of this pathway remain unclear. Here we show that LPS-treated DC metabolize tryptophan as far as quinolinate. We found that IDO contributes to LPS and TNF-alpha + poly(I:C)induced DC maturation since IDO inhibition using two different inhibitors impairs DC maturation. IDO knock-down using short-hairpin RNA also led to diminished LPS-induced maturation. In line with these results, the tryptophan-derived catabolites 3-hydroxyanthranilic acid and 3-hydroxykynurenine increased maturation of LPS-treated DC. Concerning the molecular mechanisms of this effect, IDO acts as an intermediate pathway in LPS-induced production of reactive oxygen species and NF-kappa B activation, two processes that lead to DC maturation. Finally, we show that mature DC expand CD4(+)CD25(high) regulatory T cells in an IDO-dependent manner. In conclusion, we show that IDO constitutes an intermediate pathway in DC maturation leading to expansion of CD4(+)CD25(high) regulatory T cells.