Interferon gamma-resistant mutants are defective in the induction of indoleamine 2,3-dioxygenase.

Several mutants of the human cell line ME-180 resistant to the cytotoxic effect of interferon gamma (IFN-gamma) were isolated after mutagenesis with nitrosoguanidine. Two of the mutant lines (ME-IR3b and ME-IR6g) examined had significantly lower induction levels of the L-tryptophan (L-Trp) degradative enzyme indoleamine 2,3-dioxygenase activity in response to IFN-gamma. Moreover, culture medium supplemented with low concentrations of L-Trp reversed the cytotoxic effect of IFN-gamma, whereas higher concentrations of L-Trp in the medium were extremely toxic to both parental and mutant cells. These mutants were still protected against herpes simplex virus infection by IFN-gamma and expressed the HLA-DR alpha gene normally in the presence of this lymphokine. Thus, the mutation in these cells is specific to indoleamine 2,3-dioxygenase and not a global effect of an IFN-gamma-induced gene. This genetic evidence indicates that the major pathway of IFN-gamma cytotoxicity in this cell line is mediated primarily by induction of indoleamine 2,3-dioxygenase and deprivation of L-Trp.