INHIBITION OF CELLULAR RESPONSIVENESS TO INTERFERON-GAMMA (IFN-GAMMA) INDUCED BY OVEREXPRESSION OF INACTIVE FORMS OF THE IFN-GAMMA RECEPTOR

Herein, we report that overexpression of either human or murine interferon-gamma (IFNgamma) receptors lacking their entire intracellular domains in cells bearing functionally active IFNgamma receptors ablates responsiveness to homologous ligand in a dominant negative manner. Unresponsiveness could also be induced in murine cells overexpressing murine IFNgamma receptor mutants that either lack 39 COOH-terminal amino acids or contain an alanine substitution for a functionally critical tyrosine. Overexpression of the full-length receptor did not alter cellular responsiveness to IFNgamma. The inhibitory activities of the receptor mutants were dose-dependent, generalizable to a variety of cellular responses, and specific. Cells expressing 100:1 ratios of mutant to wild-type receptor were unresponsive to IFNgamma even at doses 30,000 times greater than that required to induce a maximal response in wild-type cells. These results provide an example of a dominant negative mutation that effects the complete inactivation of a transmembrane receptor lacking a kinase domain and suggest a more general utility for dominant negative mutations in the study of cytokine receptor function.