Inhibition of T cell-mediated cytolysis by 2-deoxy-D-glucose:dissociation of the inhibitory effect from glycoprotein synthesis.
Previous studies have established that T cell-mediated cytolysis can be reversibly inhibited by the hexose analogue 2-deoxy-D-glucose (2-DG) by a mechanism which is apparently unrelated to energy depletion. The possibility that the inhibitory effect of 2-DG on cytolysis was linked to its known inhibitory effect on glycoprotein synthesis was therefore investigated. In contrast to the results obtained with 2-DG, no inhibition of cytolysis was observed in the presence of tunicamycin, a potent and specific inhibitor of lipid carrier-dependent protein glycosylation. Furthermore, populations of cytolytic cells which had been pretreated with doses of tunicamycin sufficient to block the incorporation of mannose (or 2-DG) into glycoproteins were still fully susceptible to inhibition by 2-DG. Other known inhibitors of viral protein glycosylation, such as glucosamine and galactosamine, inhibited cytolysis only weakly under conditions where 2-DG was highly effective. Kinetic studies revealed that the inhibitory effect of 2-DG on cytolysis could be reversed within minutes by the addition of exogenous glucose. Furthermore, suggestive evidence was obtained that inhibition cytolysis by 2-DG was linked to a parallel inhibition of effector: target cell binding. Taken together, these results strongly suggest that the inhibitory effect of 2-DG on cytolysis can be dissociated from its effect on protein glycosylation. An alternative mechanism of action of 2-DG is suggested.
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D003837:Deoxy Sugars / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology*; D005688:Galactosamine / Q000494:pharmacology; D005944:Glucosamine / Q000494:pharmacology; D006023:Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000276:immunology*; D013997:Time Factors; D014415:Tunicamycin / Q000494:pharmacology
D003837:Deoxy Sugars; D006023:Glycoproteins; D014415:Tunicamycin; D005688:Galactosamine; D003847:Deoxyglucose; D005944:Glucosamine