Control of tetrahydrobiopterin synthesis in T lymphocytes by synergistic action of interferon-gamma and interleukin-2.

The control of (6R)-5,6,7,8-tetrahydrobiopterin (H4biopterin) synthesis in primed T cells was analyzed by using the human T cell leukemia virus type I (HTLV-I)-transformed T cell line MT-2. In contrast to the slowly progressing induction of H4biopterin synthesis during activation of resting T cells, it is completed during a 59-h period and is directed by a synergism of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2). Both GTP cyclohydrolase and (6R)-(1',2'-dioxopropyl)-5,6,7,8-tetrahydropterin synthase activities are induced by IFN-gamma. They are further enhanced by combined treatment with IL-2, which per se is ineffective. Furthermore, the combined treatment synchronizes the time periods of both maximum activities, now extending from 33 to 44 h. This period correlates with high cellular H4biopterin levels. It is preceded by a fast and transient period of H4biopterin increase which depends on the synergistic action of both IFN-gamma and IL-2. It coincides with a transient increase in sepiapterin reductase activity. In contrast to MT-2 cells, HTLV-I-transformed HUT 102 cells constitutively secrete IFN-gamma and express IFN-gamma mRNA. The accumulation of H4biopterin is suppressed by anti-IFN-gamma polyclonal antibody and correlates with constitutive expression of all H4 biopterin-synthesizing enzymes.