The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.

Autor: Cronin SJF; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA., Seehus C; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA., Weidinger A; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria., Talbot S; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Québec, Canada., Reissig S; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Seifert M; Department of Internal Medicine II (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria., Pierson Y; Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Centre of Competence in Research (NCCR) in Chemical Biology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland., McNeill E; Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK., Longhi MS; Division of Gastroenterology and Liver Center, Department of Medicine, Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS), Harvard University, Boston, MA, USA., Turnes BL; LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Kreslavsky T; Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.; Karolinska Institute, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden., Kogler M; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Hoffmann D; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Ticevic M; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., da Luz Scheffer D; LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Tortola L; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Cikes D; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Jais A; Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany., Rangachari M; Department of Neurosciences, Centre de Recherche de CHU de Québec-Université Laval, Québec, Québec, Canada.; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Quebec, Canada., Rao S; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria., Paolino M; Karolinska Institute, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden., Novatchkova M; Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria., Aichinger M; Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria., Barrett L; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA., Latremoliere A; Neurosurgery Department, Johns Hopkins School of Medicine, Baltimore, MD, USA., Wirnsberger G; Apeiron Biologics AG, Vienna, Austria., Lametschwandtner G; Apeiron Biologics AG, Vienna, Austria., Busslinger M; Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria., Zicha S; Quartet Medicine, 400 Technology Square, Cambridge, MA, USA., Latini A; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil., Robson SC; Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK., Waisman A; Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany., Andrews N; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA., Costigan M; Department of Neurobiology, Harvard Medical School, Boston, MA, USA.; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.; Department of Anesthesia, Harvard Medical School, Boston, MA, USA.; Boston Children's Hospital, Boston, MA, USA., Channon KM; Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.; Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK., Weiss G; Department of Internal Medicine II (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria., Kozlov AV; Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria., Tebbe M; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Quebec, Canada., Johnsson K; Institute of Chemical Sciences and Engineering, Institute of Bioengineering, National Centre of Competence in Research (NCCR) in Chemical Biology, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.; Department of Chemical Biology, Max-Planck Institute for Medical Research, Heidelberg, Germany., Woolf CJ; Department of Neurobiology, Harvard Medical School, Boston, MA, USA. clifford.woolf@childrens.harvard.edu.; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA. clifford.woolf@childrens.harvard.edu., Penninger JM; IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. josef.penninger@imba.oeaw.ac.at.
Jazyk: angličtina
Zdroj: Nature [Nature] 2018 Nov; Vol. 563 (7732), pp. 564-568. Date of Electronic Publication: 2018 Nov 07.
DOI: 10.1038/s41586-018-0701-2
Abstrakt: Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain 1,2 . Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogates T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augments responses by CD4- and CD8-expressing T cells, increasing their antitumour activity in vivo. Administration of BH4 to mice markedly reduces tumour growth and expands the population of intratumoral effector T cells. Kynurenine-a tryptophan metabolite that blocks antitumour immunity-inhibits T cell proliferation in a manner that can be rescued by BH4. Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity.
Databáze: MEDLINE
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