Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action.
In the induction of an immune response, IL-15Ralpha on APCs transpresents IL-15 to NK and CD8(+)/CD44(high) T cells that express the IL-2/15Rbeta and gammac subunits only. In this study, we show data mimicking this transpresentation by using IL-15 preassociated with a chimeric protein that is comprised of the extracellular domain of murine IL-15Ralpha and the Fc portion of human IgG1. When tested in vitro, IL-15Ralpha-IgG1-Fc strongly increased the IL-15-mediated proliferation of murine NK and CD8(+)/CD44(high) T cells. The effect of IL-15Ralpha-IgG1-Fc was dependent on the presence of both IgG1-Fc and IL-15Ralpha. When injected into mice, IL-15Ralpha-IgG1-Fc enhanced the capacity of IL-15 to expand the number of NK and CD8(+)/CD44(high) T cells. The effect on cell numbers in vivo also depended on Fc receptor binding because reduced expansion was observed in FcRgamma(-/-) mice. NK cells cultured in IL-15/IL-15Ralpha-IgG1-Fc complex gained cytotoxic activity toward a number of NK-sensitive targets. When mice bearing the NK-sensitive syngeneic tumor B16 were treated, the presence of IL-15Ralpha-IgG1-Fc increased the antitumor activity of IL-15. Thus, a preassociation with IL-15Ralpha-IgG1-Fc enhances the activities of IL-15 in vivo and in vitro that may be useful in the treatment of tumors.
Dubois
Sigrid
S
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Patel
Hiral J
HJ
Zhang
Meili
M
Waldmann
Thomas A
TA
Müller
Jürgen R
JR
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D019409:Interleukin-15 / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000502:physiology; D016176:T-Lymphocyte Subsets; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology*
D000970:Antineoplastic Agents; D018960:Hyaluronan Receptors; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins