Kynurenine induces T cell fat catabolism and has limited suppressive effects in vivo
Peter J. Siska,
Jing Jiao,
Carina Matos,
Katrin Singer,
Raffaela S. Berger,
Katja Dettmer,
Peter J. Oefner,
Michelle D. Cully,
Zhonglin Wang,
William J. QuinnIII,
Kristen N. Oliff,
Benjamin J. Wilkins,
Lanette M. Christensen,
Liqing Wang,
Wayne W. Hancock,
Joseph A. Baur,
Matthew H. Levine,
Ines Ugele,
Roman Mayr,
Kathrin Renner,
Liang Zhou,
Marina Kreutz,
Ulf H. Beier
Affiliations
Peter J. Siska
Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
Jing Jiao
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, PA 19104, USA
Carina Matos
Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany
Katrin Singer
Department of Otorhinolaryngology, University Hospital Regensburg, 93053 Regensburg, Germany
Raffaela S. Berger
Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany
Katja Dettmer
Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany
Peter J. Oefner
Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany
Michelle D. Cully
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, PA 19104, USA
Zhonglin Wang
Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
William J. QuinnIII
Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA
Kristen N. Oliff
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
Benjamin J. Wilkins
Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104 USA
Lanette M. Christensen
Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
Liqing Wang
Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
Wayne W. Hancock
Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
Joseph A. Baur
Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA
Matthew H. Levine
Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA
Ines Ugele
Department of Otorhinolaryngology, University Hospital Regensburg, 93053 Regensburg, Germany
Roman Mayr
Department of Urology, Caritas St. Josef Medical Centre, University of Regensburg, Regensburg, Germany
Kathrin Renner
Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany
Liang Zhou
Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
Marina Kreutz
Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany
Ulf H. Beier
Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, PA 19104, USA; Current affiliation: Janssen Research and Development, Spring House, 19477 PA, USA; Correspondence: Dr. Ulf H. Beier
Background: L-kynurenine is a tryptophan-derived immunosuppressive metabolite and precursor to neurotoxic anthranilate and quinolinate. We evaluated the stereoisomer D-kynurenine as an immunosuppressive therapeutic which is hypothesized to produce less neurotoxic metabolites than L-kynurenine. Methods: L-/D-kynurenine effects on human and murine T cell function were examined in vitro and in vivo (homeostatic proliferation, colitis, cardiac transplant). Kynurenine effects on T cell metabolism were interrogated using [13C] glucose, glutamine and palmitate tracing. Kynurenine was measured in tissues from human and murine tumours and kynurenine-fed mice. Findings: We observed that 1 mM D-kynurenine inhibits T cell proliferation through apoptosis similar to L-kynurenine. Mechanistically, [13C]-tracing revealed that co-stimulated CD4+ T cells exposed to L-/D-kynurenine undergo increased β-oxidation depleting fatty acids. Replenishing oleate/palmitate restored effector T cell viability. We administered dietary D-kynurenine reaching tissue kynurenine concentrations of 19 μM, which is close to human kidney (6 μM) and head and neck cancer (14 μM) but well below the 1 mM required for apoptosis. D-kynurenine protected Rag1–/– mice from autoimmune colitis in an aryl-hydrocarbon receptor dependent manner but did not attenuate more stringent immunological challenges such as antigen mismatched cardiac allograft rejection. Interpretation: Our dietary kynurenine model achieved tissue concentrations at or above human cancer kynurenine and exhibited only limited immunosuppression. Sub-suppressive kynurenine concentrations in human cancers may limit the responsiveness to indoleamine 2,3-dioxygenase inhibition evaluated in clinical trials. Funding: The study was supported by the NIH, the Else Kröner-Fresenius-Foundation, Laffey McHugh foundation, and American Society of Nephrology.
