Transgenic expression of human IL15 in NOD-scid IL2rg^null (NSG) mice enhances the development and survival of functional human NK cells

Abstract

Human NK cells have critical roles in tumor surveillance and in immunoregulation within the tumor microenvironment. The balance between effector and regulatory NK cell subsets has been studied extensively in murine models of cancer, but there is a paucity of models to study human NK cell function. Humanized mice are a powerful alternative to study of human immuno-oncology and have proven effective tools to test immunotherapies targeting T cells. However human NK cell development and survival in humanized mice are severely limited. Based on previous studies showing the importance of human IL15 for NK cell development, we established NSG mice that constitutively expresses human IL15 (7.1 ± 0.3 pg/ml). To evaluate human NK cell development, 8 to 12-week-old NSG and NSG-Tg(Hu-IL15) mice were irradiated and injected intravenously with CD34+ HSC derived from umbilical cord blood. Levels of circulating human CD45+ cells, T cells and B cells were similar between the HSC-engrafted NSG-Tg(Hu-IL15) and NSG mice. Significantly higher levels of human CD56+ NK cells were found in NSG-Tg(Hu-IL15) mice as compared to NSG mice at all time points and in all tissues tested. A higher proportion of human CD56+ NK cells recovered from the blood and spleen of NSG-Tg(Hu-IL15) mice expressed granzyme A, granzyme B and perforin as compared to NK cells from NSG mice, suggesting that the NK cells were functional. Moreover, human NK cells enriched from the NSG-Tg(Hu-IL15) mice lysed K562 cells in an in vitro cytotoxicity assay. These data demonstrate that HSC-engrafted NSG mice expressing human IL15 support enhanced development of functional human NK cells and suggest that HSC-engrafted NSG-Tg(Hu-IL15) mice are a powerful model to study human NK cells.