Skip to content
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Menu
Home
About Us
Resources
Profiles Metrics
Authors Directory
Institutions Directory
Top Authors
Top Institutions
Top Sponsors
AI Digest
Contact Us
Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
general
The metabolite BH4 controls T cell proliferation in autoimmunity and cancer
Nature, Volume 563, No. 7732, Year 2018
Notification
URL copied to clipboard!
Description
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. © 2018, Springer Nature Limited.
Authors & Co-Authors
Cronin, Shane J.F.
Austria, Vienna
Institute of Molecular Biotechnology, Vienna
United States, Boston
Harvard Medical School
United States, Boston
Boston Children's Hospital
Seifert, Markus
Austria, Innsbruck
Medizinische Universitat Innsbruck
Kogler, Melanie
Austria, Vienna
Institute of Molecular Biotechnology, Vienna
Hoffmann, David
Austria, Vienna
Institute of Molecular Biotechnology, Vienna
Tortola, Luigi
Austria, Vienna
Institute of Molecular Biotechnology, Vienna
Cikes, Domagoj
Austria, Vienna
Institute of Molecular Biotechnology, Vienna
Rao, Shuan
Austria, Vienna
Institute of Molecular Biotechnology, Vienna
Novatchkova, Maria
Austria, Vienna
Research Institute of Molecular Pathology, Vienna
Busslinger, Meinrad
Austria, Vienna
Research Institute of Molecular Pathology, Vienna
Robson, Simon Christopher
United Kingdom, London
British Heart Foundation
United Kingdom, Oxford
University of Oxford
Waisman, Ari
Germany, Mainz
Universitätsmedizin Mainz
Andrews, Nick Arthur
United States, Boston
Harvard Medical School
United States, Boston
Boston Children's Hospital
Costigan, Michael
United States, Boston
Harvard Medical School
United States, Boston
Boston Children's Hospital
Channon, Keith Michael
United Kingdom, London
British Heart Foundation
United Kingdom, Oxford
University of Oxford
Weiss, Günter
Austria, Innsbruck
Medizinische Universitat Innsbruck
Johnsson, Kai P.
Switzerland, Lausanne
École Polytechnique Fédérale de Lausanne
Germany, Heidelberg
Max Planck Institute for Medical Research
Woolf, Clifford J.
United States, Boston
Harvard Medical School
United States, Boston
Boston Children's Hospital
Penninger, Josef M.
Austria, Vienna
Institute of Molecular Biotechnology, Vienna
Statistics
Citations: 158
Authors: 18
Affiliations: 18
Identifiers
Doi:
10.1038/s41586-018-0701-2
ISSN:
00280836
Research Areas
Cancer
Genetics And Genomics
Study Design
Cross Sectional Study