Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO

被引:145
作者
Belladonna, Maria L.
Grohmann, Ursula
Guidetti, Paolo
Volpi, Claudia
Bianchi, Roberta
Fioretti, Maria C.
Schwarcz, Robert
Fallarino, Francesca
Puccetti, Paolo
机构
[1] Univ Perugia, Dept Expt Med, Sect Pharmacol, I-06126 Perugia, Italy
[2] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA
关键词
D O I
10.4049/jimmunol.177.1.130
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Dendritic cell (DC) tryptophan catabolism has emerged in recent years as a major mechanism of peripheral tolerance. However, there are features of this mechanism, initiated byIDO, that are still unclear, including the role of enzymes that are downstream of IDO in the kynurenine pathway and the role of the associated production of kynurenines. In this study, we provide evidence that 1) murine DCs express all enzymes necessary for synthesis of the downstream product of tryptophan breakdown, quinolinate; 2) IFN-gamma enhances transcriptional expression of all of these enzymes, although posttranslational inactivation of IDO may prevent metabolic steps that area subsequent and consequent to IDO; 3) overcoming the IDO-dependent blockade by provision of a downstream quinolinate precursor activates the pathway and leads to the onset of suppressive properties; and 4) tolerogenic DCs can confer suppressive ability on otherwise immunogenic DCs across a Transwell in an IDO-dependent fashion. Altogether, these data indicate that kynurenine pathway enzymes downstream of IDO can initiate tolerogenesis by DCs independently of tryptophan deprivation. The paracrine production of kynurenines might be one mechanism used by IDO-competent cells to convert DCs lacking functional IDO to a tolerogenic phenotype within an IFN-gamma-rich environment.
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页码:130 / 137
页数:8
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