Functional Characterization of the Human Interleukin-15 Receptor αChain and Close Linkage of IL15RA and IL2RA Genes

Abstract

Interleukins-2 and −15 (IL-2 and IL-15) are cytokines with overlapping but distinct biological effects. Their receptors share two subunits (the IL-2Rβ and -γ chains) that are essential for signal transduction. The IL-2 receptor requires an additional IL-2-specific α subunit for high affinity IL-2 binding. Recently, a murine IL-15-specific α subunit was identified, cloned, and shown to be structurally related to IL-2Rα. However, the murine IL-15Rα alone bound IL-15 with a 1000-fold higher affinity than that seen with IL-2Rα and IL-2. We now extend these studies into the human system with the isolation of three differentially spliced human IL-15Rα variants that are all capable of high affinity binding of IL-15. The cytoplasmic domain of IL-15Rα, like that of IL-2Rα, is dispensable for mitogenic signaling, suggesting that the primary role of the α chains is to confer high affinity binding. At high concentrations, IL-15, like IL-2, is able to signal through a complex of IL-2Rβ and -γ in the absence of the α subunit. Furthermore, the IL15RA and IL2RA genes have a similar intron-exon organization and are closely linked in both human and murine genomes. However, the distribution of expression of the IL-15Rα is much wider than that of the IL-2Rα, suggesting a broader range of cellular targets for IL-15. Interleukins-2 and −15 (IL-2 and IL-15) are cytokines with overlapping but distinct biological effects. Their receptors share two subunits (the IL-2Rβ and -γ chains) that are essential for signal transduction. The IL-2 receptor requires an additional IL-2-specific α subunit for high affinity IL-2 binding. Recently, a murine IL-15-specific α subunit was identified, cloned, and shown to be structurally related to IL-2Rα. However, the murine IL-15Rα alone bound IL-15 with a 1000-fold higher affinity than that seen with IL-2Rα and IL-2. We now extend these studies into the human system with the isolation of three differentially spliced human IL-15Rα variants that are all capable of high affinity binding of IL-15. The cytoplasmic domain of IL-15Rα, like that of IL-2Rα, is dispensable for mitogenic signaling, suggesting that the primary role of the α chains is to confer high affinity binding. At high concentrations, IL-15, like IL-2, is able to signal through a complex of IL-2Rβ and -γ in the absence of the α subunit. Furthermore, the IL15RA and IL2RA genes have a similar intron-exon organization and are closely linked in both human and murine genomes. However, the distribution of expression of the IL-15Rα is much wider than that of the IL-2Rα, suggesting a broader range of cellular targets for IL-15.