The Metabolite BH4 Drives T-cell Growth in Autoimmunity and Cancer

Tetrahydrobiopterin (BH4) is a cofactor of enzymes involved in neurotransmitter biosynthesis and nitric oxide production: expression of the enzyme GCH1, the first enzyme in the BH4 biosynthesis pathway, is elevated in activated T cells. To further elucidate the role of BH4 in T-cell biology, Cronin and colleagues generated mice with Gch1-ablated T cells. Gch1 loss resulted in decreased CD4⁺ and CD8⁺ T-cell proliferation but did not affect T-cell development or early T-cell activation events. Infusion of Gch1-depleted CD4⁺ T cells into an immunodeficient mouse model of colitis or various mouse models of autoimmunity, such as allergic airway inflammation or autoimmune encephalitis, decreased inflammation compared to controls. Similarly, pharmacologic inhibition of SPR, the terminal enzyme in the BH4 biosynthesis pathway, with SPRi3 resulted in decreased BH4 levels in CD4⁺ T cells and decreased inflammation in mouse models of colitis and allergic airway inflammation. Further, SPRi3 treatment reduced the proliferation of activated human CD4⁺ effector T cells and decreased inflammation in vivo. Expression of genes related to iron homeostasis was increased in activated Gch1-depleted CD4⁺ T cells compared to activated controls, and iron levels were decreased in activated Gch1-depleted CD4⁺ T cells. Given the role of iron transporters in mitochondrial respiration, mitochondrial respiration was measured and shown to be decreased in activated Gch1-depleted CD4⁺ T cells compared to activated controls. Mitochondrial electron transport chain function was impaired in activated Gch1-depleted CD4⁺ T cells and was rescued by the addition of reduced ferrocytochrome c. Overexpressing Gch1 in T cells or BH4 supplementation increased T-cell proliferation and enhanced in vivo T cell–dependent antitumor immunity. Moreover, a small-molecule inhibitor of SPR, QM385, was developed and shown to exhibit higher potency than SPRi3 in vitro and in vivo. These results elucidate the role of BH4 in T-cell biology and suggest that BH4 supplementation may enhance immunotherapeutic efficacy.

Cronin SJ, Seehus C, Weidinger A, Talbot S, Reissig S, Seifert M, et al. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 2018 Nov 7 [Epub ahead of print].

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