COOPERATIVE INTERACTIONS BETWEEN THE INTERLEUKIN-2 RECEPTOR-ALPHA AND BETA-CHAINS ALTER THE INTERLEUKIN-2-BINDING AFFINITY OF THE RECEPTOR SUBUNITS

The interleukin 2 (IL-2) receptor (IL-2R) is a multisubunit receptor that includes three major IL-2 binding subunits, the IL-2R alpha, beta, and gamma chains. We have detected and analyzed cooperative interactions between the IL-2R alpha and beta chains (IL-2Ralpha and IL2Rbeta, respectively) in COS cells transfected with cDNAs encoding the IL-2Ralpha, the IL-2Rbeta, or both cDNAs. We demonstrated that IL-2 F42A, an analog that fails to bind to the isolated IL-2Ralpha subunit and would be predicted by the hierarchical affinity-conversion model to have impaired binding to cells expressing both chains, instead readily binds to the IL-2Ralpha/beta heterodimer in COS cells. Furthermore, this binding is abolished by the antibody HIEI that separates the two IL-2R subunits. The monoclonal antibodies anti-Tac and Mik-beta1 directed at the IL-2-binding sites on IL-2Ralpha and IL-2Rbeta, respectively; block ligand binding to the heterodimer. This binding pattern is inconsistent with the strict hierarchical affinity-conversion model that mandates an initial binding of IL-2 to IL-2Ralpha followed by binding of the IL-2/IL-2Ralpha complex to IL-2Rbeta. Instead, our results support an alternative model of preformed complexes of IL-2Rbeta with other IL-2R subunits. In this alternative model, IL-2Ralpha and -beta exist in part as preformed complexes in which the affinity of IL-2Rbeta for IL-2 is altered by the proximity of IL-2Ralpha, through mechanisms that do not require the prior binding of IL-2 to IL-2Ralpha.