The discovery and molecular characterization of interleukin-2 (IL-2) has had a considerable impact on basic and clinical immunology (Morgan et al., 1976; Taniguchi et al., 1963; Rosenberg et al., 1965). The IL-2 system has been extensively studied in the context of the clonal proliferation of T cells and has become a paradigm of how interleukins and other soluble mediators, collectively termed cytokines, function in the development and regulation of the immune system. The proliferation of matured, resting T cells is initiated via signal transduction, in which the specific interaction of the antigen-major histocompatibility complex molecule with the Tcell antigen receptor complex (TCR) induces the expression of IL-2 and its homologous receptor. In effect, this IL-2-induced cell proliferative response is a key determinant affecting the magnitude of the immune response. IL-2 is also known to function in other lymphoid cell types, including thymocytes and B cells, as well as in some nonlymphoid cells (reviewed in Smith, 1964; Greene and Leonard, 1966; Shimizu et al., 1966; Waldmann, 1969; Minami et al., 1993a). More recently, it has been reported that IL-2 also programs T cells to undergo apoptosis following TCR stimulation (Lenardo, 1991).

The IL-2 receptor is unique among growth factor receptors in that it is made up of at least three distinct membrane components: the a chain (IL-2Ra), the 6 chain (IL-PR6), and the y chain (IL-PRY). The genes encoding these components have been cloned and characterized. Expression of the genes encoding IL-2Ra and the IL-2 ligand are undetectable in resting T cells but are efficiently induced upon T cell activation. The IL-2Rj3 gene is expressed constitutively in CD6’cytotoxic T cells but not in CD4+ helper T cells; the IL-2R3 gene is further induced upon T cell activation, whereas IL9RT is expressed constitutively in lymphoid cells (see reviews; Takeshita et al., 1992). IL9R6 and IL-PRY, but not IL-2Ra, belong to a newly identified superfamily of cytokine receptors, characterized by four conserved cysteines and the sequence WSXWS (the WS motif)(Figure 1). In humans, expression of different combinations of these three components gives rise to the generation of various forms of the IL-2 receptor, each of which manifests different binding affinities to IL-2. As shown in Table 1, the combination of the 6 and y chains is required for signal transduction, but reconstitution of the high affinity (Kd= 10-l’M) form of the IL-2 receptor requires the additional participation of the a chain. It has been proposed that IL-2 binding may induce conformational changes in the IL-2 receptor component chains,