The metabolite BH4 controls T cell proliferation in autoimmunity and cancer

Shane J. F. Cronin, Corey Seehus, Adelheid Weidinger, Sebastien Talbot, Sonja Reissig, Markus Seifert, Yann Pierson, Eileen McNeill, Maria Serena Longhi, Bruna Lenfers Turnes, Taras Kreslavsky, Melanie Kogler, David Hoffmann, Melita Ticevic, Débora Scheffer, Luigi Tortola, Domagoj Cikes, Alexander Jais, Manu Rangachari, Shuan Rao, Magdalena Paolino, Maria Novatchkova, Martin Aichinger, Lee Barrett, Alban Latremoliere, Gerald Wirnsberger, Guenther Lametschwandtner, Meinrad Busslinger, Stephen Zicha, Alexandra Latini, Simon C. Robson, Ari Waisman, Nick Andrews, Michael Costigan, Keith M. Channon, Guenter Weiss, Andrey V. Kozlov, Mark Tebbe, Kai Johnsson, Clifford J. Woolf () and Josef M. Penninger ()
Additional contact information
Shane J. F. Cronin: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Corey Seehus: Harvard Medical School
Adelheid Weidinger: AUVA Research Center
Sebastien Talbot: Harvard Medical School
Sonja Reissig: University Medical Center of the Johannes Gutenberg-University Mainz
Markus Seifert: Immunology, Rheumatology and Pneumology), Medical University of Innsbruck
Yann Pierson: National Centre of Competence in Research (NCCR) in Chemical Biology, École Polytechnique Fédérale de Lausanne (EPFL)
Eileen McNeill: University of Oxford
Maria Serena Longhi: Harvard University
Bruna Lenfers Turnes: Universidade Federal de Santa Catarina
Taras Kreslavsky: Research Institute of Molecular Pathology, Vienna Biocenter
Melanie Kogler: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
David Hoffmann: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Melita Ticevic: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Débora Scheffer: Universidade Federal de Santa Catarina
Luigi Tortola: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Domagoj Cikes: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Alexander Jais: Max Planck Institute for Metabolism Research
Manu Rangachari: Centre de Recherche de CHU de Québec–Université Laval, Québec
Shuan Rao: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Magdalena Paolino: Karolinska University Hospital Solna
Maria Novatchkova: Research Institute of Molecular Pathology, Vienna Biocenter
Martin Aichinger: Research Institute of Molecular Pathology, Vienna Biocenter
Lee Barrett: Harvard Medical School
Alban Latremoliere: Johns Hopkins School of Medicine
Gerald Wirnsberger: Apeiron Biologics AG
Guenther Lametschwandtner: Apeiron Biologics AG
Meinrad Busslinger: Research Institute of Molecular Pathology, Vienna Biocenter
Stephen Zicha: Quartet Medicine
Alexandra Latini: Harvard Medical School
Simon C. Robson: University of Oxford
Ari Waisman: University Medical Center of the Johannes Gutenberg-University Mainz
Nick Andrews: Harvard Medical School
Michael Costigan: Harvard Medical School
Keith M. Channon: University of Oxford
Guenter Weiss: Immunology, Rheumatology and Pneumology), Medical University of Innsbruck
Andrey V. Kozlov: AUVA Research Center
Mark Tebbe: Faculty of Medicine, Université Laval
Kai Johnsson: National Centre of Competence in Research (NCCR) in Chemical Biology, École Polytechnique Fédérale de Lausanne (EPFL)
Clifford J. Woolf: Harvard Medical School
Josef M. Penninger: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences

Nature, 2018, vol. 563, issue 7732, 564-568

Abstract: 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.

Keywords: Sepiapterin Reductase (SPR); Kynurenine; TBS Tris-buffered Saline (TBST); House Dust Mite; Solutol HS (search for similar items in EconPapers)
Date: 2018
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DOI: 10.1038/s41586-018-0701-2

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