Nature (London), 2018-11, Vol.563 (7732), p.564-568
- 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.
2018
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- Autor(en) / Beteiligte
- 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.
- Titel
- The metabolite BH4 controls T cell proliferation in autoimmunity and cancer
- Ist Teil von
- Nature (London), 2018-11, Vol.563 (7732), p.564-568
- Ort / Verlag
- London: Nature Publishing Group UK
- Erscheinungsjahr
- 2018
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0028-0836, 1476-4687eISSN: 1476-4687DOI: 10.1038/s41586-018-0701-2Titel-ID: cdi_swepub_primary_oai_prod_swepub_kib_ki_se_139701673
- Format
- –
- Schlagworte
- 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