Tryptophan hydroxylase-1 regulates immune tolerance and inflammation

被引:101
作者
Nowak, Elizabeth C. [1 ,2 ]
de Vries, Victor C. [1 ,2 ]
Wasiuk, Anna [1 ,2 ]
Ahonen, Cory [1 ,2 ]
Bennett, Kathryn A. [1 ,2 ]
Le Mercier, Isabelle [1 ,2 ]
Ha, Dae-Gon [1 ,2 ]
Noelle, Randolph J. [1 ,2 ,3 ]
机构
[1] Dartmouth Med Sch, Dept Microbiol & Immunol, Lebanon, NH 03756 USA
[2] Norris Cotton Canc Ctr, Lebanon, NH 03756 USA
[3] Kings Coll London, Guys Hosp, Kings Hlth Partners, Med Res Council Ctr Transplantat, London SE1 9RT, England
基金
英国医学研究理事会; 美国国家卫生研究院;
关键词
T-CELL TOLERANCE; MAST-CELLS; INDOLEAMINE 2,3-DIOXYGENASE; ALLOGRAFT TOLERANCE; DENDRITIC CELLS; SEROTONIN; INHIBITION; ACTIVATION; RESPONSES; MEDIATOR;
D O I
10.1084/jem.20120408
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control inflammatory responses and immune tolerance. Here we report the novel finding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 deficiency breaks allograft tolerance, induces tumor remission, and intensifies neuroinflammation, respectively. All of these effects of Tph-1 deficiency are independent of its downstream product serotonin. Because mast cells (MCs) appear to be the major source of Tph-1 and restoration of Tph-1 in the MC compartment in vivo compensates for the defect, these experiments introduce a fundamentally new mechanism of MC-mediated immune suppression that broadly impacts multiple arms of immunity.
引用
收藏
页码:2127 / 2135
页数:9
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