The metabolite BH4 controls T cell proliferation in autoimmunity and cancer

• Published in: Nature (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
• Language: English
• Published: London Nature Publishing Group UK 01.11.2018; Nature Publishing Group
• Subjects: 631/250/1619/554; 631/250/251/1574; 631/250/2520; 631/250/38; 64; 64/60; 96/31; Administration, Oral; Alcohol Oxidoreductases - antagonists & inhibitors; Alcohol Oxidoreductases - metabolism; Anemia; Animals; Anticancer properties; Antigens; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; Autoimmune Diseases - pathology; Autoimmunity; Bioenergetics; Biology; Biopterins - analogs & derivatives; Biopterins - biosynthesis; Biopterins - metabolism; Biopterins - pharmacology; Cancer; CD4 antigen; CD8 antigen; Cell activation; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cells (Biology); Coenzymes - metabolism; Deactivation; Effector cells; Environmental effects; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzymes; Female; Gene expression; Genetic engineering; GTP cyclohydrolase; GTP Cyclohydrolase - genetics; GTP Cyclohydrolase - metabolism; Guanosine triphosphate; Homeostasis; Humanities and Social Sciences; Humans; Hypersensitivity; Hypersensitivity - immunology; Immunity; Inactivation; Inflammation; Inflammatory bowel disease; Iron; Iron - metabolism; Kynurenine - metabolism; Kynurenine - pharmacology; Letter; Lymphocytes; Lymphocytes T; Male; Medical schools; Medicin och hälsovetenskap; Metabolism; Metabolites; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondria - metabolism; Monoamines; multidisciplinary; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - pathology; Neurophysiology; Neurotransmitters; Nitric oxide; Nitrogen oxides; Pain; Physiological aspects; Regulators; Sapropterin dihydrochloride; Science; Science (multidisciplinary); Sepiapterin reductase; Synthesis; T cell receptors; T cells; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tetrahydrobiopterin; Tryptophan; Tumors; Kynurenine; Sepiapterin Reductase (SPR); TBS Tris-buffered Saline (TBST); Solutol HS; House Dust Mite
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-018-0701-2

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.