The Fantastic BH4 matters in T cells

Tetrahydrobiopterin (BH4) is an essential cofactor in the biosynthesis of molecules regulating neurotransmission and vascular tone. In a recent publication, Cronin and colleagues discovered a novel role of BH4 in regulating T cell immunity.  

Cells generate BH4 through de novo synthesis catalyzed mainly by GTP cyclohydrolase I (GCH1) and sepiapterin reductase (SPR). Through modulating the de novo synthesis pathway, Cronin et al. addressed the roles of BH4 in T cells. They found out by using genetically engineered mice that loss of GCH1 in T cells abrogates proliferation without affecting T cell development or activation markers. Through using models of inflammatory and autoimmune diseases, the authors showed that lowering BH4 levels through genetic ablation of GCH1 or pharmacological inhibition of SPR downgrades the severity and signs of injury. They attributed the effect of GCH1 loss to changes in iron redox status, which in turn controls the mitochondrial function and energy production, required for T cell proliferation. Supplementing T cells with BH4 or the BH4 precursor sepiapterin, could reverse the impact of GCH1 deficiency. As expected, the ability of BH4 to expand the effector T cell population was sufficient to reduce tumor burden in T cell-dependent cancer models. Collectively, the study established a role of BH4 in T cell proliferation involved in a range of pathological conditions. 

For future studies and translational applications, BH4 supplementation could be combined with adoptive cell transfer and immunotherapy to enhance their efficacy. In addition, data presented could provide new hypotheses to the mechanisms of methotrexate, an antineoplastic and anti-inflammatory drug. Since methotrexate strikingly decreases BH4 levels, it is unknown whether this could adversely affect T cells in cancer patients treated with methotrexate. In such case, exogenous BH4 may provide a worthwhile benefit. Overall, this study provides tremendous opportunities to improve the efficacy of current immunotherapeutic and anti-cancer treatment modalities.

A highlight and Commentary by Asmaa El-Kenawi for Research Article:

Cronin SJF, 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;563(7732):564-8.