Metabolic requirements for expanding and arming a clone army

Abstract

A new target to control T cell responses involves de novo biosynthesis of tetrahydrobiopterin (BH4), adding to the list of processes dependent on BH4 synthesis, which includes neurotransmitter and nitric oxide production and pain control.T cells are the storm troopers of the immune system since they can kill other cells.Consequently, T cells must be licensed to expand and bear arms through a tightly regulated process 1 . A recent study in Nature by Cronin et al. reveal a critical role for the enzyme cofactor tetrahydrobiopterin (BH4) in licensing T cell clones to proliferate and acquire weapons of destruction 2 . These findings add to the extensive list of biological functions mediated by BH4, including production of neurotransmitters, nitric oxide and pain control.Circulating T cells are metabolically inert. On activation, T cells proliferate rapidly and acquire effector functions, including, in the case of cytotoxic T cells, the ability to destroy target cells (Fig. 1). This licensing process has strict requirements for coordinated delivery of activation signals from antigens, co-stimulatory ligands and pro-inflammatory cytokines 1 . These constraints ensure that potentially dangerous effector T cells are generated only as needed. Cronin et al.report that de novo, cell-intrinsic, BH4 synthesis is necessary for T cells to undergo clonal expansion. The initial prompt was the observation that activated T cells expressed GTP cyclohydrolase I (GCH1), the first step in BH4 synthesis 2 . Gch1-deficient mice were generated and activated T cells from these mice exhibited profound proliferative defects in vitro and in vivo,