Predominant development of mature and functional human NK cells in a novel human IL-2-producing transgenic NOG mouse

• Published in: The Journal of immunology (1950) Vol. 194; no. 7; pp. 3513 - 3525
• Main Authors: Katano, Ikumi, Takahashi, Takeshi, Ito, Ryoji, Kamisako, Tsutomu, Mizusawa, Takuma, Ka, Yuyo, Ogura, Tomoyuki, Suemizu, Hiroshi, Kawakami, Yutaka, Ito, Mamoru
• Format: Journal Article
• Language: English
• Published: United States 01.04.2015
• Subjects: Animals; Antibody-Dependent Cell Cytotoxicity; Antigens, Surface - metabolism; Cell Differentiation; Cytotoxicity, Immunologic; Disease Models, Animal; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - metabolism; Humans; Immunophenotyping; Interleukin-2 - biosynthesis; Interleukin-2 - genetics; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Mice; Mice, Transgenic; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Phenotype; Receptors, KIR - genetics; Receptors, KIR - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1401323

We generated a severe immunodeficient NOD/Shi-scid-IL-2Rγ(null) (NOG) mouse substrain expressing the transgenic human IL-2 gene (NOG-IL-2 Tg). Upon transfer of human cord blood-derived hematopoietic stem cells (HSCs), CD3(-)CD56(high)CD16(+/-) cells developed unexpectedly, predominantly in the NOG-IL-2 Tg (hu-HSC NOG-IL-2 Tg). These cells expressed various NK receptors, including NKp30, NKp44, NKp46, NKG2D, and CD94, as well as a diverse set of killer cell Ig-like receptor molecules at levels comparable to normal human NK cells from the peripheral blood, which is evidence of their maturity. They produced levels of granzyme A as high as in human peripheral blood-derived NK cells, and a considerable amount of perforin protein was detected in the plasma. Human NK cells in hu-HSC NOG-IL-2 Tg produced IFN-γ upon stimulation, and IL-2, IL-15, or IL-12 treatment augmented the in vitro cytotoxicity. Inoculation of K562 leukemia cells into hu-HSC NOG-IL-2 Tg caused complete rejection of the tumor cells, whereas inoculation into hu-HSC NOG fully reconstituted with human B, T, and some NK cells did not. Moreover, when a CCR4(+) Hodgkin's lymphoma cell line was inoculated s.c. into hu-HSC NOG-IL-2 Tg, the tumor growth was significantly suppressed by treatment with a therapeutic humanized anti-CCR4 Ab (mogamulizumab), suggesting that the human NK cells in the mice exerted active Ab-dependent cellular cytotoxicity in vivo. Taken together, these data suggest that the new NOG-IL-2 Tg strain is a unique model that can be used to investigate the biological and pathological functions of human NK cells in vivo.