FcepsilonRI induces the tryptophan degradation pathway involved in regulating T cell responses.
FcepsilonRI is suspected to play a pivotal role in the pathophysiology of atopic disorders such as atopic dermatitis. In search for genes differentially regulated by FcepsilonRI on APCs, a differential cDNA bank of receptor-stimulated and unstimulated monocytes was established. By means of suppression subtractive hybridization, we identified kynurenine 3-monooxygenase and subsequently indoleamine 2,3-dioxygenase (IDO) to be overexpressed in FcepsilonRI-activated monocytes. IDO is the rate-limiting enzyme in the catabolism of the essential amino acid tryptophan. We show that cross-linking of FcepsilonRI on monocytes results in low tryptophan concentrations associated with impaired T cell stimulatory capacity. Importantly, T cell suppression could be prevented by the addition of tryptophan or inhibition of IDO. Moreover, stimulation of T cells by FcepsilonRI-activated monocytes was increased compared with T cell stimulation by nonactivated monocytes if exogenous supply of tryptophan was available. We speculate that the expression of IDO by FcepsilonRI(+) APCs in vivo allows these cells to regulate T cell responses in atopic disorders by inhibiting or stimulating T cell proliferation, depending on the metabolic environment.
von Bubnoff
Dagmar
D
Department of Dermatology, University of Bonn, Bonn, Germany. d.bubnoff@uni-bonn.de
Matz
Heike
H
Frahnert
Christine
C
Rao
Marie Luise
ML
Hanau
Daniel
D
de la Salle
Henri
H
Bieber
Thomas
T
D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016753:Interleukin-10 / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase; D008213:Lymphocyte Activation / Q000187:drug effects; D006899:Mixed Function Oxygenases / Q000235:genetics; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017455:Receptors, IgE / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D014366:Tryptophan Oxygenase / Q000037:antagonists & inhibitors / Q000235:genetics
D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D017455:Receptors, IgE; D016753:Interleukin-10; D014364:Tryptophan; D006899:Mixed Function Oxygenases; D014366:Tryptophan Oxygenase; D050601:Kynurenine 3-Monooxygenase