IL-4 receptor complexes containing or lacking the gamma C chain are inhibited by an overlapping set of antagonistic IL-4 mutant proteins.

IL-4 signals on lymphocytes and other cells through a heterodimeric complex of two cytokine receptor proteins, IL-4R alpha and gamma C. IL-4 variants with mutations in the positions Tyr124, and (less efficiently) Arg121 and Ser125 are deficient in interaction with gamma zero and can be applied as IL-4 antagonists. Some cells respond to IL-4 without using gamma zero presumably by recruiting an alternative subunit into the receptor complex. We have investigated the effects of IL-4 mutant proteins on cells bearing this second type of IL-4 receptor complex. Mutations in the amino acid residues Arg 121 and Tyr124, but not Ser125, completely prevented cellular responses mediated by type 2 IL-4 receptors. Both receptor types are therefore affected by mutations in an overlapping but not identical site of the IL-4 molecule.