Regulation of thymocyte proliferation and survival by deoxynucleosides. Deoxycytidine produced by thymic accessory cells protects thymocytes from deoxyguanosine toxicity and stimulates their spontaneous proliferation.
Deoxyguanosine (dGuo) inhibits thymic blast DNA synthesis and then induces thymocyte cell death. The dGuo inhibitory action, measured with four different assays (spontaneous thymidine incorporation, immunofluorescent detection of 5-bromodeoxyuridine incorporation, dye exclusion, tetrazolium salt cleavage), was suppressed in the presence of supernatants from cultures containing phagocytic cells. In particular, we studied the anti-dGuo activity in supernatants from thymic reticulum cultures (TRS) and in those from phagocytic cells isolated from TR cultures (P-TR). The anti-dGuo substance was identified as deoxycytidine (dCyd) by high performance liquid chromatography and other physicochemical studies. Secretion of dCyd by P-TR is accompanied by thymidine but not by purine nucleoside secretion. A dual mechanism of thymocyte rescue by dCyd was demonstrated by a study of the dose-dependencies of dCyd-mediated prevention and reversal, respectively, of the dGuo inhibition. In addition to this exogenously added anti-dGuo action, dCyd and dCyd-containing TRS induced significant stimulation of spontaneous thymic blast proliferation, and the kinetics of both effects were identical. These findings might suggest that a major role of thymic phagocytic cells is the supply of pyrimidine nucleosides to thymocytes resulting in the maintenance of proliferation and protection of at least some thymic blasts from the toxic effects of dGTP accumulation. The role of this system in the intrathymic selection process is discussed.
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival; D004261:DNA Replication / Q000187:drug effects; D003841:Deoxycytidine / Q000494:pharmacology* / Q000502:physiology; D003849:Deoxyguanosine / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D005455:Fluorescent Antibody Technique; D008222:Lymphokines / Q000096:biosynthesis / Q000494:pharmacology; D051379:Mice; D013936:Thymidine / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects
D008222:Lymphokines; D003841:Deoxycytidine; D001973:Bromodeoxyuridine; D003849:Deoxyguanosine; D013936:Thymidine