High dose CD11c-driven IL15 is sufficient to drive NK cell maturation and anti-tumor activity in a trans-presentation independent manner.

Julia K Polansky,Diego A Goyeneche-Patino,Erwin H Duitman,Zane Orinska,Christina Vock,Mylene Divivier,Rajia Bahri,Silvia Bulfone-Paus

doi:10.1038/srep19699

Abstract

The common gamma (γc)-chain cytokine interleukin 15 (IL15) is a multifunctional immune-modulator which impacts the generation, maturation and activity of many cell types of the innate, as well as the adaptive immune system, including natural killer (NK) and CD8+ T cells. Using a new series of transgenic mice, we analyzed the in vivo potential of IL15 as an immune-regulator when available at different concentrations or delivery modes, i.e. soluble monomer or complexed to its specific receptor α (Rα)-chain. We have identified distinct effects on selected IL15-responsive populations. While CD8+ T cells required complexed forms of IL15/IL15Rα for full functionality, mature NK populations were rescued in an IL15/IL15Rα-deficient environment by high levels of CD11c-restricted IL15. These IL15-conditions were sufficient to limit tumor formation in a lung metastasis model indicating that the NK cell populations were fully functional. These data underline the potential of “free” IL15 in the absence of Rα-complex as a powerful and specific immuno-modulator, which may be beneficial where selective immune-activation is desired.

Highlights

The common gamma-chain cytokine interleukin 15 (IL15) is a multifunctional immune-modulator which impacts the generation, maturation and activity of many cell types of the innate, as well as the adaptive immune system, including natural killer (NK) and CD8+ T cells
There were no detectable levels of free IL15 in bone marrow-derived dendritic cells (BMDCs) lysates derived from transgenic mouse strains 64, 65 and 69, with levels comparable to that of values obtained from Il15−/− BMDC lysates, used here as a negative control for the assay
This control was essential as the ELISA for IL15 appears to be more sensitive in its detection of recombinant IL15 compared with naturally occurring IL15, as can be seen by the high background levels in our BMDC lysates (Fig. 1A)

Summary

Introduction

The common gamma (γc)-chain cytokine interleukin 15 (IL15) is a multifunctional immune-modulator which impacts the generation, maturation and activity of many cell types of the innate, as well as the adaptive immune system, including natural killer (NK) and CD8+ T cells. While CD8+ T cells required complexed forms of IL15/IL15Rα for full functionality, mature NK populations were rescued in an IL15/IL15Rα-deficient environment by high levels of CD11c-restricted IL15. These IL15conditions were sufficient to limit tumor formation in a lung metastasis model indicating that the NK cell populations were fully functional. These data underline the potential of “free” IL15 in the absence of Rα-complex as a powerful and specific immuno-modulator, which may be beneficial where selective immune-activation is desired. It has been shown that IL15 complex formation with IL15Rα prolongs the bioavailability of recombinant IL1514

Methods

Results

Conclusion