Paracrine and transpresentation functions of IL-15 are mediated by diverse splice versions of IL-15Rα in human monocytes and dendritic cells.
BACKGROUND
IL-15 can either be transpresented by IL-15Rα or be secreted.


RESULTS
New N- and C-terminal splice versions of human IL-15Rα determine whether IL-15 is secreted or stays bound to the cell membrane.


CONCLUSIONS
IL-15Rα isoforms determine the mode of action of IL-15.


CONCLUSIONS
IL-15Rα isoforms may modify immune response outcomes in humans. Species-specific differences of post-translational modifications suggested the existence of human IL-15Rα isoforms. We identified eight new isoforms that are predicted to modify the intracellular C termini of IL-15Rα, 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-15Rα 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-15Rα that explained the species-specific differences. The Ex2A domain appeared to be removed from major IL-15Rα species during protein maturation, but both Ex2A and IL-15Rα 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-15Rα complexes were readily released from cells that expressed IL-15/IL-15Rα-IC3 thus limiting this IL-15/IL-15Rα isoform to act as a secreted molecule. These data suggest that splice versions of IL-15Rα determine the range of IL-15 activities.
Metabolism Branch, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
Jürgen R
JR
Müller
Thomas A
TA
Waldmann
Michael J
MJ
Kruhlak
Sigrid
S
Dubois
D020816:Amino Acid Motifs; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism*; D006801:Humans; D019409:Interleukin-15 / Q000235:genetics / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D019899:Paracrine Communication; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D012326:RNA Splicing
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D020033:Protein Isoforms