The metabolite BH4 controls T cell proliferation in autoimmunity and cancer


Senior Member
Cronin, Seehus, Penninger
November, 2018

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.


Senior Member
Pacific Northwest
Wow, that's a great find. Thanks for posting. BH4 is used in several processes and there are multiple genes that either promote it's production or recycling. Fairly common mutations in any of them may lead to tetrahydrobiopterin (BH4) deficiency, which can impact neurotransmitter production, peroxynitrite production, amount of nitric oxide which can impact blood pressure, urea cycle function,

as well as this article which can impact T cells, cancer, and autoimmunity.

One doesn't need to have mutations in the main PKU gene, PAH, to have a problem. Mutations in GCH1, QDPR, PCBD1, PTS, and SPR can lead to lower levels of BH4, neurotransmitters, nitric oxide and higher levels of peroxynitrites which cause mitochondrial membrane damage and impaired mito complex 1.

The specialty drug Kuvan can increase BH4 and lead to improvement. It comes in a stabilized powdered form which can be dissolved in water to provide flexible dosing.