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Preassociation of IL-15 with IL-15R-IgG1-Fc Enhances Its Activity on Proliferation of NK and CD8⁺/CD44^high T Cells and Its Antitumor Action¹

Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892

In the induction of an immune response, IL-15R on APCs transpresents IL-15 to NK and CD8⁺/CD44^high T cells that express the IL-2/15Rβ and c 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-15R and the Fc portion of human IgG1. When tested in vitro, IL-15R-IgG1-Fc strongly increased the IL-15-mediated proliferation of murine NK and CD8⁺/CD44^high T cells. The effect of IL-15R-IgG1-Fc was dependent on the presence of both IgG1-Fc and IL-15R. When injected into mice, IL-15R-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 FcR^–/– mice. NK cells cultured in IL-15/IL-15R-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-15R-IgG1-Fc increased the antitumor activity of IL-15. Thus, a preassociation with IL-15R-IgG1-Fc enhances the activities of IL-15 in vivo and in vitro that may be useful in the treatment of tumors.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the intramural research program of the National Cancer Institute, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Jürgen Müller, Metabolism Branch, National Cancer Institute, National Institutes of Health, Building 10 Room 4N109, 10 Center Drive, Bethesda, MD 20892. E-mail address: muellerj{at}mail.nih.gov

³ Abbreviations used in this paper: DC, dendritic cell; sIL-15 complex, soluble IL-15/IL-15R-IgG1-Fc complex; WT, wild type.

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