HETERODIMERIZATION OF THE IL-2 RECEPTOR BETA-CHAIN AND GAMMA-CHAIN CYTOPLASMIC DOMAINS IS REQUIRED FOR SIGNALING

THE interaction of interleukin-2 (IL-2) and IL-2 receptors critically regulates the T-cell immune response following antigen activation(1,2) . IL-2 can signal through high or intermediate affinity receptors whic h contain IL-2R alpha (refs 3, 4) + beta (refs 5-8) + gamma (ref. 9) o r beta + gamma chains, respectively. IL-2R gamma is a common gamma cha in, gamma(c), also shared by the IL-7 (ref. 10) and IL-4 (refs 11, 12) receptors, which when mutated results in X-linked severe combined imm unodeficiency(13). Using chimaeric receptor constructs together with m onoclonal or bispecific antibodies we demonstrate here that IL-2 signa lling requires ligand-induced extracellular-domain-mediated heterodime rization of the beta- and gamma(c)-chain cytoplasmic domains. Anti-IL- 2R alpha monoclonal antibodies trigger proliferation of cells transfec ted with chimaeric constructs in which the extracellular domains of IL -2R beta and gamma(c), are replaced by that of IL-2R alpha. Other expe riments using chimaeric constructs indicated that IL-2 binds monomeric ally and monovalently to IL-2R alpha and that the beta-transmembrane d omain is not required for receptor chain interactions. Finally, we pro vide a method for mapping residues in the gamma(c) cytoplasmic domain even in cells that constitutively express gamma(c).