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Paracrine and transpresentation functions of IL-15 are mediated by diverse splice versions of IL-15R? in human monocytes and dendritic cells.

ABSTRACT: IL-15 can either be transpresented by IL-15R? or be secreted.New N- and C-terminal splice versions of human IL-15R? determine whether IL-15 is secreted or stays bound to the cell membrane.IL-15R? isoforms determine the mode of action of IL-15.IL-15R? isoforms may modify immune response outcomes in humans. Species-specific differences of post-translational modifications suggested the existence of human IL-15R? isoforms. We identified eight new isoforms that are predicted to modify the intracellular C termini of IL-15R?, 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? 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? that explained the species-specific differences. The Ex2A domain appeared to be removed from major IL-15R? species during protein maturation, but both Ex2A and IL-15R? 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? complexes were readily released from cells that expressed IL-15/IL-15R?-IC3 thus limiting this IL-15/IL-15R? isoform to act as a secreted molecule. These data suggest that splice versions of IL-15R? determine the range of IL-15 activities.

SUBMITTER: Muller JR

PROVIDER: S-EPMC3504748 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Paracrine and transpresentation functions of IL-15 are mediated by diverse splice versions of IL-15Rα in human monocytes and dendritic cells.

Müller Jürgen R JR Waldmann Thomas A TA Kruhlak Michael J MJ Dubois Sigrid S

The Journal of biological chemistry 20121016 48

<h4>Background</h4>IL-15 can either be transpresented by IL-15Rα or be secreted.<h4>Results</h4>New N- and C-terminal splice versions of human IL-15Rα determine whether IL-15 is secreted or stays bound to the cell membrane.<h4>Conclusion</h4>IL-15Rα isoforms determine the mode of action of IL-15.<h4>Significance</h4>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 ...[more]

PMID: 23074221

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Project description:BackgroundInterleukin-15 (IL-15) is a critical cytokine for the development, proliferation, and function of natural killer (NK) cells, NKT cells, and CD8+ memory T cells and has become one of the most promising protein molecules for the treatment of cancer and viral diseases. However, there are several limitations in applying IL-15 in therapy, such as its low yield in vitro, limited potency, and short half-life in vivo. To date, there are several recombinant IL-15 agonists based on configurational modifications that are being pursued in the treatment of cancer, such as ALT-803, which are mainly produced from mammalian cells.ResultsIn this study, we designed two different forms of the IL-15 complex, which were formed by the noncovalent assembly of IL-15 with dimeric or monomeric sushi domain of IL-15 receptor α (SuIL-15Rα)-IgG4 Fc fusion protein and designated IL-15/SuIL-15Rα-dFc and IL-15/SuIL-15Rα-mFc, respectively. The two IL-15 complexes were expressed in Pichia pastoris (P. pastoris), and their activities and half-lives were evaluated and compared. Pharmacokinetic analysis showed that IL-15/SuIL-15Rα-dFc had a half-life of 14.26 h while IL-15/SuIL-15Rα-mFc had a half-life of 9.16 h in mice, which were much longer than the 0.7-h half-life of commercial recombinant human IL-15 (rhIL-15). Treatment of mice with intravenous injection of the two IL-15 complexes resulted in significant increases in NK cells, NKT cells, and memory CD8+ T cells, which were not observed after rhIL-15 treatment. Treatment of human peripheral blood mononuclear cells (PBMCs) from healthy donors with the two IL-15 complexes yielded enhanced NK and CD8+ T cell activation and proliferation, which was comparable to the effect of rhIL-15.ConclusionsThese findings indicate that the IL-15/SuIL-15Rα-dFc and IL-15/SuIL-15Rα-mFc produced in P. pastoris exhibit potent activities and prolonged half-lives and may serve as superagonists for immunotherapy in further research and applications.

Dataset Information

Paracrine and transpresentation functions of IL-15 are mediated by diverse splice versions of IL-15R? in human monocytes and dendritic cells.

Publications

Paracrine and transpresentation functions of IL-15 are mediated by diverse splice versions of IL-15Rα in human monocytes and dendritic cells.

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