Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation.
Marrow stromal cells (MSCs) inhibit allogeneic T-cell responses, yet the molecular mechanism mediating this immunosuppressive effect of MSCs remains controversial. Recently, expression of indoleamine 2,3-dioxygenase (IDO), which is induced by interferon-gamma (IFN-gamma) and catalyzes the conversion from tryptophan to kynurenine, has been identified as a T-cell inhibitory effector pathway in professional antigen-presenting cells. Here we show that human MSCs express IDO protein and exhibit functional IDO activity upon stimulation with IFN-gamma. MSCs inhibit allogeneic T-cell responses in mixed lymphocyte reactions (MLRs). Concomitantly, IDO activity resulting in tryptophan depletion and kynurenine production is detected in MSC/MLR coculture supernatants. Addition of tryptophan significantly restores allogeneic T-cell proliferation, thus identifying IDO-mediated tryptophan catabolism as a novel T-cell inhibitory effector mechanism in human MSCs. As IDO-mediated T-cell inhibition depends on MSC activation, modulation of IDO activity might alter the immunosuppressive properties of MSCs in different therapeutic applications.
Clinic of Pediatric Oncology, Hematology and Immunology, University Hospital, Moorenstrasse 5, D-40225 Düsseldorf, Germany.
Roland
R
Meisel
Andree
A
Zibert
Maurice
M
Laryea
Ulrich
U
Göbel
Walter
W
Däubener
Dagmar
D
Dilloo
D001854:Bone Marrow Cells / Q000166:cytology*; D002478:Cells, Cultured; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology; D008213:Lymphocyte Activation; D017154:Stromal Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000235:genetics* / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase