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Nature. 2018 Nov;563(7732):564-568. doi: 10.1038/s41586-018-0701-2. Epub 2018 Nov 7.

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

Author information

1
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
2
Department of Neurobiology, Harvard Medical School, Boston, MA, USA.
3
FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
4
Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Center, Vienna, Austria.
5
Département de Pharmacologie et Physiologie, Université de Montréal, Montréal, Québec, Canada.
6
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.
7
Department of Internal Medicine II (Infectious Diseases, Immunology, Rheumatology and Pneumology), Medical University of Innsbruck, Innsbruck, Austria.
8
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.
9
Division of Cardiovascular Medicine, British Heart Foundation Centre for Research Excellence, John Radcliffe Hospital, University of Oxford, Oxford, UK.
10
Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford, UK.
11
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.
12
LABOX, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Florianópolis, Brazil.
13
Research Institute of Molecular Pathology, Vienna Biocenter, Campus-Vienna-Biocenter 1, Vienna, Austria.
14
Karolinska Institute, Department of Medicine Solna, Center for Molecular Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.
15
Department of Neuronal Control of Metabolism, Max Planck Institute for Metabolism Research, Cologne, Germany.
16
Department of Neurosciences, Centre de Recherche de CHU de Québec-Université Laval, Québec, Québec, Canada.
17
Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Quebec, Canada.
18
Neurosurgery Department, Johns Hopkins School of Medicine, Baltimore, MD, USA.
19
Apeiron Biologics AG, Vienna, Austria.
20
Quartet Medicine, 400 Technology Square, Cambridge, MA, USA.
21
Department of Anesthesia, Harvard Medical School, Boston, MA, USA.
22
Boston Children's Hospital, Boston, MA, USA.
23
Department of Chemical Biology, Max-Planck Institute for Medical Research, Heidelberg, Germany.
24
Department of Neurobiology, Harvard Medical School, Boston, MA, USA. clifford.woolf@childrens.harvard.edu.
25
FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA. clifford.woolf@childrens.harvard.edu.
26
IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria. josef.penninger@imba.oeaw.ac.at.

Abstract

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 pain1,2. 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.

PMID:
30405245
DOI:
10.1038/s41586-018-0701-2

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