Siska, Peter J. and Jiao, Jing and Matos, Carina and Singer, Katrin and Berger, Raffaela S. and Dettmer, Katja and Oefner, Peter J. and Cully, Michelle D. and Wang, Zhonglin and Quinn, William J. and Oliff, Kristen N. and Wilkins, Benjamin J. and Christensen, Lanette M. and Wang, Liqing and Hancock, Wayne W. and Baur, Joseph A. and Levine, Matthew H. and Ugele, Ines and Mayr, Roman and Renner, Kathrin and Zhou, Liang and Kreutz, Marina and Beier, Ulf H. (2021) YY Kynurenine induces T cell fat catabolism and has limited suppressive effects in vivo. EBIOMEDICINE, 74: 103734. ISSN 2352-3964
Full text not available from this repository. (Request a copy)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 [C-13] 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, [C-13]-tracing revealed that co-stimulated CD4(+) T cells exposed to L-/D-kynurenine undergo increased beta-oxidation depleting fatty acids. Replenishing oleate/palmitate restored effector T cell viability. We administered dietary D-kynurenine reaching tissue kynurenine concentrations of 19 mM, which is close to human kidney (6 mM) and head and neck cancer (14 mM) 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. (C) 2021 The Author(s). Published by Elsevier B.V.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ARYL-HYDROCARBON RECEPTOR; IMMUNE-RESPONSES; METABOLISM; TRYPTOPHAN; ACID; INDUCTION; SURVIVAL; COLITIS; T cell metabolism; immunosuppression; tumour microenvironment; indoleamine-2,3-dioxygenase; cancer metabolism; aryl hydrocarbon receptor |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Hals-Nasen-Ohren-Heilkunde Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Urologie Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 05 Jul 2022 06:31 |
| Last Modified: | 05 Jul 2022 06:31 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46880 |
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