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  The metabolite BH4 controls T cell proliferation in autoimmunity and cancer

Cronin, S. J. F., Seehus, C., Weidinger, A., Talbot, S., Reissig, S., Seifert, M., et al. (2018). The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature, 563, 564-568. doi:10.1038/s41586-018-0701-2.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0002-721A-1 Version Permalink: http://hdl.handle.net/21.11116/0000-0002-C1B3-9
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 Creators:
Cronin, Shane J. F., Author
Seehus, Corey, Author
Weidinger, Adelheid, Author
Talbot, Sebastien, Author
Reissig, Sonja, Author
Seifert, Markus, Author
Pierson, Yann, Author
McNeill, Eileen, Author
Longhi, Maria Serena, Author
Turnes, Bruna Lenfers, Author
Kreslavsky, Taras, Author
Kogler, Melanie, Author
Hoffmann, David, Author
Ticevic, Melita, Author
da Scheffer, Débora Luz, Author
Tortola, Luigi, Author
Cikes, Domagoj, Author
Jais, Alexander, Author
Rangachari, Manu, Author
Rao, Shuan, Author
Paolino, Magdalena, AuthorNovatchkova, Maria, AuthorAichinger, Martin, AuthorBarrett, Lee, AuthorLatremoliere, Alban, AuthorWirnsberger, Gerald, AuthorLametschwandtner, Guenther, AuthorBusslinger, Meinrad, AuthorZicha, Stephen, AuthorLatini, Alexandra, AuthorRobson, Simon C., AuthorWaisman, Ari, AuthorAndrews, Nick, AuthorCostigan, Michael, AuthorChannon, Keith M., AuthorWeiss, Guenter, AuthorKozlov, Andrey V., AuthorTebbe, Mark, AuthorJohnsson, Kai1, Author              Woolf, Clifford J., AuthorPenninger, Josef M., Author more..
Affiliations:
1Chemical Biology, Max Planck Institute for Medical Research, Max Planck Society, ou_2364732              

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 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.

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Language(s): eng - English
 Dates: 2018-11-072018-11-072018-11-22
 Publication Status: Published in print
 Pages: 32
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1038/s41586-018-0701-2
 Degree: -

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Title: Nature
  Abbreviation : Nature
Source Genre: Journal
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Publ. Info: London : Nature Publishing Group
Pages: - Volume / Issue: 563 Sequence Number: - Start / End Page: 564 - 568 Identifier: ISSN: 0028-0836
CoNE: https://pure.mpg.de/cone/journals/resource/954925427238