Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation

Wei Chen, Li Li, Torben Brod, Omar Saeed, Salim Thabet, Thomas Jansen, Sergey Dikalov, Cornelia Weyand, Jorg Goronzy, David G. Harrison

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Tetrahydrobiopterin (BH4) is an essential co-factor for the nitric-oxide (NO) synthases, and in its absence these enzymes. produce superoxide (O2) rather than NO. The rate-limiting enzyme for BH4 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 BH4 levels. Resting T cells had minimal expression of inducible NOS (NOS2), endothelial NOS (NOS3), and GTPCH-1 protein and nearly undetectable levels of BH4. 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 BH4 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(1mmol/liter) prevented T cell BH4 accumulation, reduced NO production, and increased T cell O2 production, due to both NOS2 and NOS3 uncoupling. GTPCH-1 inhibition also promoted TH2 polarization in memory CD4 cells. Ovalbumin immunization of mice transgenic for an ovalbumin receptor (OT-II mice) confirmed a marked increase in T cell BH4in vivo. These studies identify a previously unidentified consequence of T cell activation, promoting BH4 levels, NO production, and modulating T cell cytokine production.

Original languageEnglish (US)
Pages (from-to)13846-13851
Number of pages6
JournalJournal of Biological Chemistry
Volume286
Issue number16
DOIs
StatePublished - Apr 22 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Chen, W., Li, L., Brod, T., Saeed, O., Thabet, S., Jansen, T., Dikalov, S., Weyand, C., Goronzy, J., & Harrison, D. G. (2011). Role of increased guanosine triphosphate cyclohydrolase-1 expression and tetrahydrobiopterin levels upon T cell activation. Journal of Biological Chemistry, 286(16), 13846-13851. https://doi.org/10.1074/jbc.M110.191023