Toll-like receptor engagement enhances the immunosuppressive properties of human bone marrow-derived mesenchymal stem cells by inducing indoleamine-2,3-dioxygenase-1 via interferon-beta and protein kinase R.
Mesenchymal stem cells (MSC) display unique suppressive properties on T-cell immunity, thus representing an attractive vehicle for the treatment of conditions associated with harmful T-cell responses such as organ-specific autoimmunity and graft-versus-host disease. Toll-like receptors (TLR) are primarily expressed on antigen-presenting cells and recognize conserved pathogen-derived components. Ligation of TLR activates multiple innate and adaptive immune response pathways to eliminate and protect against invading pathogens. In this work, we show that TLR expressed on human bone marrow-derived MSC enhanced the immunosuppressive phenotype of MSC. Immunosuppression mediated by TLR was dependent on the production of immunosuppressive kynurenines by the tryptophan-degrading enzyme indoleamine-2,3-dioxygenase-1 (IDO1). Induction of IDO1 by TLR involved an autocrine interferon (IFN)-beta signaling loop, which was dependent on protein kinase R (PKR), but independent of IFN-gamma. These data define a new role for TLR in MSC immunobiology, which is to augment the immunosuppressive properties of MSC in the absence of IFN-gamma rather than inducing proinflammatory immune response pathways. PKR and IFN-beta play a central, previously unidentified role in orchestrating the production of immunosuppressive kynurenines by MSC.
Department of Neurooncology, University Hospital of Heidelberg and German Cancer Research Center, Heidelberg, Germany.
Christiane A
CA
Opitz
Ulrike M
UM
Litzenburger
Christian
C
Lutz
Tobias V
TV
Lanz
Isabel
I
Tritschler
Alexandra
A
Köppel
Eva
E
Tolosa
Maik
M
Hoberg
Jan
J
Anderl
Wilhelm K
WK
Aicher
Michael
M
Weller
Wolfgang
W
Wick
Michael
M
Platten
D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology* / Q000378:metabolism; D007737:Kynurenine / Q000096:biosynthesis / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism; D019892:eIF-2 Kinase / Q000276:immunology* / Q000378:metabolism
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051193:Toll-Like Receptors; D007737:Kynurenine; D016899:Interferon-beta; D019892:eIF-2 Kinase