Paracrine and Transpresentation Functions of IL-15 Are Mediated by Diverse Splice Versions of IL-15Rα in Human Monocytes and Dendritic Cells

Species-specific differences of post-translational modifications suggested the existence of human IL-15R alpha isoforms. We identified eight new isoforms that are predicted to modify the intracellular C termini of IL-15R alpha, and another N-terminal exon Ex2A that was consistently present in all but one of the C-terminal isoforms. Ex2A encodes a 49-amino acid domain that allowed the transfer of IL-15/IL-15R alpha complex to the cell surface but prevented its cleavage from cell membranes and its secretion thus facilitating the transpresentation of IL-15 as part of the immunological synapse. The Ex2A domain also affected the O-glycosylation of IL-15R alpha that explained the species-specific differences. The Ex2A domain appeared to be removed from major IL-15R alpha species during protein maturation, but both Ex2A and IL-15R alpha appeared on the surface of monocytic cells upon activation. The membrane-associated form of the only C-terminal isoform that lacked Ex2A (IC3) was retained inside the cell, but soluble IL-15/IL-15R alpha complexes were readily released from cells that expressed IL-15/IL-15R alpha-IC3 thus limiting this IL-15/IL-15R alpha isoform to act as a secreted molecule. These data suggest that splice versions of IL-15R alpha determine the range of IL-15 activities.