FUNCTIONAL-CHARACTERIZATION OF THE HUMAN INTERLEUKIN-15 RECEPTOR-ALPHA CHAIN AND CLOSE LINKAGE OF IL15RA AND IL2RA GENES

Interleukins-2 and -15 (IL-2 and IL-15) are cytokines with overlapping but distinct biological effects. Their receptors share two subunits ( the IL-2R beta and -gamma chains) that are essential for signal transd uction. The IL-2 receptor requires an additional IL-2-specific alpha s ubunit for high affinity IL-2 binding, Recently, a murine IL-15-specif ic alpha subunit was identified, cloned, and shown to be structurally related to IL-2R alpha. However, the murine IL-15R alpha alone bound I L-15 with a 1000-fold higher affinity than that seen with IL-2R alpha and IL-2. We now extend these studies into the human system with the i solation of three differentially spliced human IL-15R alpha variants t hat are all capable of high affinity binding of IL-15. The cytoplasmic domain of IL-15R alpha, like that of IL-2R alpha, is dispensable for mitogenic signaling, suggesting that the primary role of the alpha cha ins is to confer high affinity binding. At high concentrations, IL-15, like P2, is able to signal through a complex of IL-2R beta and -gamma in the absence of the cu subunit. Furthermore, the IL15RA and IL2RA g enes have a similar intron-exon organization and are closely linked in both human and murine genomes. However, the distribution of expressio n of the lL-15R alpha is much wider than that of the IL-2R alpha, sugg esting a broader range of cellular targets for IL-15.