An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells.
The aryl hydrocarbon receptor (AHR) has been known to cause immunosuppression after binding dioxin. It has recently been discovered that the receptor may be central to T cell differentiation into FoxP3(+) regulatory T cells (Tregs) versus Th17 cells. In this paper, we demonstrate that kynurenine, the first breakdown product in the IDO-dependent tryptophan degradation pathway, activates the AHR. We furthermore show that this activation leads to AHR-dependent Treg generation. We additionally investigate the dependence of TGF-beta on the AHR for optimal Treg generation, which may be secondary to the upregulation of this receptor that is seen in T cells postexposure to TGF-beta. These results shed light on the relationship of IDO to the generation of Tregs, in addition to highlighting the central importance of the AHR in T cell differentiation. All tissues and cells were derived from mice.
Mezrich
Joshua D
JD
Division of Transplantation, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792-7375, USA. mezrich@surgery.wisc.edu
Fechner
John H
JH
Zhang
Xiaoji
X
Johnson
Brian P
BP
Burlingham
William J
WJ
Bradfield
Christopher A
CA
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D007737:Kynurenine / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018336:Receptors, Aryl Hydrocarbon / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D014364:Tryptophan / Q000737:chemistry / Q000502:physiology
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008024:Ligands; D018336:Receptors, Aryl Hydrocarbon; D016212:Transforming Growth Factor beta; D007737:Kynurenine; D014364:Tryptophan