LIGAND-BINDING BY THE IL-2 RECEPTOR IS MODULATED BY INTRACELLULAR DETERMINANTS OF THE IL-2 RECEPTOR BETA-CHAIN

The biologic actions of IL-2 are mediated by the IL-2R, a multisubunit receptor complex displayed on the surface of lymphocytes and select o ther hematopoietic lineages. The IL-2R exhibits multiple affinities fo r IL-2 that result from the monomeric (alpha), heterodimeric (alpha be ta and beta gamma), and heterotrimeric (alpha beta gamma) assembly of different receptor subunits. In the present stud ies, we have used a s eries of IL-2R mutants in a transient mammalian expression system to i nvestigate the potential role of intracellular receptor regions in the ligand-binding functions of the IL-2R. Analyses of chimeric and delet ion mutants of the IL-2R beta subunit have revealed that its intracell ular domain critically and selectively influences high affinity ligand binding mediated through the extracellular domains of the clip-hetero dimeric receptor. In contrast, intermediate affinity binding of IL-2 b y beta gamma-heterodimeric receptors exhibits no dependence on the cyt oplasmic domain of IL-2R beta. Further, co-expression of either a full -length or severely truncated form of IL-2R gamma to generate an alpha beta gamma-heterotrimeric complex also overcomes the functional depen dence upon the cytoplasmic tail of IL-2R beta. Collectively, our findi ngs suggest that the cytoplasmic domain of IL-2R beta produces intrasu bunit transmembrane conformational changes in this receptor subunit th at promote extracellular IL-2 binding in combination with IL-2R alpha. These findings have important implications for the receptor dynamics involved in both ligand binding and signal transduction as well as for clinical applications pertaining to altering IL-2R function.