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

doi:10.1016/j.ebiom.2021.103734

Kynurenine induces T cell fat catabolism and has limited suppressive effects in vivo

EBioMedicine. 2021 Dec:74:103734. doi: 10.1016/j.ebiom.2021.103734. Epub 2021 Dec 4.

Authors

Peter J Siska¹, Jing Jiao², Carina Matos¹, Katrin Singer³, Raffaela S Berger⁴, Katja Dettmer⁴, Peter J Oefner⁴, Michelle D Cully², Zhonglin Wang⁵, William J QuinnIII⁶, Kristen N Oliff⁷, Benjamin J Wilkins⁸, Lanette M Christensen⁹, Liqing Wang⁹, Wayne W Hancock⁹, Joseph A Baur⁶, Matthew H Levine⁵, Ines Ugele³, Roman Mayr¹⁰, Kathrin Renner¹¹, Liang Zhou⁷, Marina Kreutz¹¹, Ulf H Beier¹²

Affiliations

¹ Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany.
² Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Otorhinolaryngology, University Hospital Regensburg, 93053 Regensburg, Germany.
⁴ Institute of Functional Genomics, University of Regensburg, 93053 Regensburg, Germany.
⁵ Department of Surgery, Penn Transplant Institute, Perelman School of Medicine, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Physiology and Institute of Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁷ Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA.
⁸ Division of Anatomic Pathology, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104 USA.
⁹ 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.
¹⁰ Department of Urology, Caritas St. Josef Medical Centre, University of Regensburg, Regensburg, Germany.
¹¹ Department of Internal Medicine III, University Hospital Regensburg, 93053 Regensburg, Germany; Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
¹² 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. Electronic address: ubeier@its.jnj.com.

Abstract

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.

Keywords: T cell metabolism; aryl hydrocarbon receptor; cancer metabolism; immunosuppression; indoleamine-2,3-dioxygenase; tumour microenvironment.

MeSH terms

Animals
Cell Line, Tumor
Cell Proliferation / drug effects
Colitis / genetics
Colitis / prevention & control*
Disease Models, Animal
Fatty Acids / metabolism*
Female
Gene Knockout Techniques
Glucose / metabolism
Homeodomain Proteins / genetics*
Humans
Immunosuppressive Agents / administration & dosage*
Immunosuppressive Agents / pharmacology
Kynurenine / administration & dosage*
Kynurenine / pharmacology
Male
Melanoma, Experimental / drug therapy*
Melanoma, Experimental / immunology
Mice
T-Lymphocytes / cytology*
T-Lymphocytes / drug effects
T-Lymphocytes / metabolism

Substances

Fatty Acids
Homeodomain Proteins
Immunosuppressive Agents
RAG-1 protein
Kynurenine
Glucose

Abstract

MeSH terms

Substances

Grants and funding