Different Human Interleukin‐4 Mutants Preferentially Activate Human or Murine Common Receptor γ Chain

Abstract

Interleukin‐4 (IL‐4) shows species‐specific activity due to species‐restricted interaction with the IL‐4 receptor α (IL‐4Rα) chain. The second subunit of a functional IL‐4 receptor, the common γ chain (γ_c), is more promiscuous, since human IL‐4 is able to activate IL‐4 receptor complexes containing either human or murine common γ receptor chain (γ_c). We have stably transfected factor‐dependent mouse cells of myeloid and lymphoid origin with combinations of human IL‐4Rα and γ_c. derivatives. In these cell lines, both human and murine γ_c receptors as well as IL‐4Rα chains from both species are simultaneously expressed. Both versions of γ_c readily form ternary complexes with either human IL‐4 and human IL‐4Rα or murine IL‐4 and murine IL‐4Rα. Due to distinct ligand‐binding properties of human and murine γ_c, the two receptor complexes can be activated preferentially by different mutant variants of human IL‐4. The contribution of murine common γ chain to human IL‐4‐induced signal transduction is suppressed by an inhibitory antibody directed to the extracellular domain of the mouse γ_c. We present evidence that the two IL‐4R complexes functionally interfere with each other and compete for response‐limiting signalling components.