The [formula omitted] receptor system: A current overview

Abstract

Tadatsugu Taniguchi and Yasuhiro Mlnami Institute for Molecular and Cellular Biology Osaka University Yamadaoka 1-3, Suita-shi Osaka 565 Japan The discovery and molecular characterization of interleu- kin-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 cyto- kines, 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 spe- cific 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 re- sponse 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 re- cently, 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 recep- tors 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 com- ponents have been cloned and characterized. Expression of the genes encoding IL-2Ra and the IL-2 ligand are unde- tectable in resting T cells but are efficiently induced upon T cell activation. The IL-2Rj3 gene is expressed constitu- tively 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 differ- ent 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