title: Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation.
abstract: Tetrahydrobiopterin (BH(4)) is an essential co-factor for the nitric-oxide (NO) synthases, and in its absence these enzymes produce superoxide (O(2)(·-)) rather than NO. The rate-limiting enzyme for BH(4) production is guanosine triphosphate cyclohydrolase-1 (GTPCH-1). Because endogenously produced NO affects T cell function, we sought to determine whether antigen stimulation affected T cell GTPCH-1 expression and ultimately BH(4) levels. Resting T cells had minimal expression of inducible NOS (NOS2), endothelial NOS (NOS3), and GTPCH-1 protein and nearly undetectable levels of BH(4). Anti-CD3 stimulation of T cells robustly stimulated the coordinated expression of NOS2, NOS3, and GTPCH-1 and markedly increased both GTPCH-1 activity and T cell BH(4) levels. The newly expressed GTPCH-1 was phosphorylated on serine 72 and pharmacological inhibition of casein kinase II reduced GTPCH-1 phosphorylation and blunted the increase in T cell BH(4). Inhibition of GTPCH-1 with diaminohydroxypyrimidine (1 mmol/liter) prevented T cell BH(4) accumulation, reduced NO production, and increased T cell O(2)(·-) production, due to both NOS2 and NOS3 uncoupling. GTPCH-1 inhibition also promoted TH(2) polarization in memory CD4 cells. Ovalbumin immunization of mice transgenic for an ovalbumin receptor (OT-II mice) confirmed a marked increase in T cell BH(4) in vivo. These studies identify a previously unidentified consequence of T cell activation, promoting BH(4) levels, NO production, and modulating T cell cytokine production.
authors.affiliation: Cardiology Division and Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Torben
authors.initials: T
authors.lastname: Brod
authors.forename: Omar
authors.initials: O
authors.lastname: Saeed
authors.forename: Salim
authors.initials: S
authors.lastname: Thabet
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansen
authors.forename: Sergey
authors.initials: S
authors.lastname: Dikalov
authors.forename: Cornelia
authors.initials: C
authors.lastname: Weyand
authors.forename: Jorg
authors.initials: J
authors.lastname: Goronzy
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D017252:CD3 Complex / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D006136:GTP Cyclohydrolase / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007156:Immunologic Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000737:chemistry; D010100:Oxygen / Q000737:chemistry; D010766:Phosphorylation; D013601:T-Lymphocytes / Q000166:cytology / Q000201:enzymology*
chemical_list: D017252:CD3 Complex; D016207:Cytokines; D001708:Biopterins; D010047:Ovalbumin; D006136:GTP Cyclohydrolase; C003402:sapropterin; D010100:Oxygen