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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

England: Nature Publishing Group

Erscheinungsjahr

2018

Link zum Volltext

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 . 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.

Sprache: Englisch
Identifikatoren: ISSN: 0028-0836, 1476-4687
eISSN: 1476-4687
DOI: 10.1038/s41586-018-0701-2
Titel-ID: cdi_pubmed_primary_30405245

Format: –
Schlagworte: 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, 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, Humans, Hypersensitivity, Hypersensitivity - immunology, Immunity, Inactivation, Inflammation, Inflammatory bowel disease, Iron, Iron - metabolism, Kynurenine - metabolism, Kynurenine - pharmacology, Lymphocytes, Lymphocytes T, Male, Medical colleges, Medical schools, Medicin och hälsovetenskap, Metabolism, Metabolites, Mice, Mice, Inbred C57BL, Mitochondria, Mitochondria - metabolism, Neoplasms - drug therapy, Neoplasms - immunology, Neoplasms - pathology, Neurophysiology, Neurotransmitters, Nitric oxide, Nitrogen oxides, Pain, Physiological aspects, Regulators, Sapropterin dihydrochloride, Sepiapterin reductase, Synthesis, T cell receptors, T cells, T-Lymphocytes - cytology, T-Lymphocytes - drug effects, T-Lymphocytes - immunology, T-Lymphocytes - metabolism, Tetrahydrobiopterin, Tryptophan, Tumors

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The metabolite BH4 controls T cell proliferation in autoimmunity and cancer

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