The metabolite BH4 controls T cell proliferation in autoimmunity and cancer

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 proce...

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Published inNature (London) Vol. 563; no. 7732; pp. 564 - 568
Main Authors Cronin, Shane J. F., Seehus, Corey, Weidinger, Adelheid, Talbot, Sebastien, Reissig, Sonja, Seifert, Markus, Pierson, Yann, McNeill, Eileen, Longhi, Maria Serena, Turnes, Bruna Lenfers, Kreslavsky, Taras, Kogler, Melanie, Hoffmann, David, Ticevic, Melita, da Luz Scheffer, Débora, Tortola, Luigi, Cikes, Domagoj, Jais, Alexander, Rangachari, Manu, Rao, Shuan, Paolino, Magdalena, Novatchkova, Maria, Aichinger, Martin, Barrett, Lee, Latremoliere, Alban, Wirnsberger, Gerald, Lametschwandtner, Guenther, Busslinger, Meinrad, Zicha, Stephen, Latini, Alexandra, Robson, Simon C., Waisman, Ari, Andrews, Nick, Costigan, Michael, Channon, Keith M., Weiss, Guenter, Kozlov, Andrey V., Tebbe, Mark, Johnsson, Kai, Woolf, Clifford J., Penninger, Josef M.
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 01.11.2018
Nature Publishing Group
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Summary: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. Tetrahydrobiopterin (BH4) is an enzyme co-factor that is involved in the nervous system; it is shown here to also function in T cell activation and proliferation, with roles in autoimmunity, allergic inflammation and cancer.
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Author contributions S.J.F.C., together with C.J.W. and J.M.P., conceived and designed the study. All experiments were performed by S.J.F.C. with the following exceptions: A.W. and A.J. performed mitochondrial respiration analyses; S.R. performed colonoscopy grading; S.T., C.S. and B.L.T. carried out the asthma model; C.S. and B.L.T. carried out the HDM model; Y.P. performed the iron-reduction experiment; M.S.L., G.L. and G.W. carried out assays for human T-cell proliferation; M.S. performed the iron measurements; T.K. performed in vitro thymocyte differentiation experiments; M.N. performed microarray analysis; E.M.N., B.L.T. and D.L.S. performed biopterin and sepiapterin measurements; M.R., M.K., D.H., M.T., L.T., D.C., S.R., M.P. and M.A. helped with the cancer studies; L.B., N.A., A.L. and M.C. helped with compound dosing and discussions of BH4 biology; M.T. and S.Z. performed QM385 pharmacokinetic analysis. S.J.F.C., C.J.W. and J.M.P. wrote the manuscript with input from all authors.
ISSN:0028-0836
1476-4687
1476-4687
DOI:10.1038/s41586-018-0701-2