Tetrahydro-4-aminobiopterin attenuates dendritic cell-induced T cell priming independently from inducible nitric oxide synthase.
Formation of NO by NO synthases (NOSs) strictly depends on tetrahydrobiopterin. Its structural analog, tetrahydro-4-aminobiopterin, is an inhibitor of all NOS isoenzymes, which prolongs allograft survival in acute murine cardiac rejection and prevents septic shock in the rat. In this study, we show that murine bone marrow-derived dendritic cells treated with tetrahydro-4-aminobiopterin had a reduced capacity to prime alloreactive murine T cells in oxidative mitogenesis. Checking for a possible influence on LPS-induced dendritic cell maturation, we found that tetrahydro-4-aminobiopterin down-regulated MHC class II expression and counteracted LPS-induced down-regulation of ICOS ligand, while expression of CD40, CD86, CD80, B7-H1, and B7-DC remained unchanged. Tetrahydro-4-aminobiopterin also reduced activation of CD4(+) T cells isolated from mice overexpressing an OVA-specific TCR by OVA-loaded murine bone marrow-derived dendritic cells, thus indicating that its effect on MHC class II expression is involved in attenuating T cell activation. In line with affecting dendritic cell function and T cell activation, tetrahydro-4-aminobiopterin impaired production of proinflammatory cytokines and the Th1 response. With regard to cell survival, tetrahydro-4-aminobiopterin induced efficient apoptosis of murine T cells but not of murine dendritic cells. Experiments with cells from inducible NOS (iNOS) knockout mice and with N(6)-(1-iminoethyl)-L-lysine, a specific inhibitor of iNOS, ruled out participation of iNOS in any of the observed effects. These findings characterize attenuation of T cell stimulatory capacity of murine bone marrow-derived dendritic cells as an immunosuppressive mechanism of tetrahydro-4-aminobiopterin that is not related to its iNOS-inhibiting properties.
Thoeni
Guntram
G
Biocenter, Division of Biological Chemistry, Department of Dermatology and Venerology, Innsbruck Medical University, Innsbruck, Austria.
Stoitzner
Patrizia
P
Brandacher
Gerald
G
Romani
Nikolaus
N
Heufler
Christine
C
Werner-Felmayer
Gabriele
G
Werner
Ernst R
ER
D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001708:Biopterins / Q000031:analogs & derivatives* / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D011621:Pteridines / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
D000954:Antigens, Surface; D016207:Cytokines; D004791:Enzyme Inhibitors; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; C090663:N(6)-(1-iminoethyl)lysine; D011621:Pteridines; C106930:4-amino-tetrahydrobiopterin; D001708:Biopterins; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine