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

Ikumi Katano, Takeshi Takahashi, Ryoji Ito, Tsutomu Kamisako, Takuma Mizusawa, Yuyo Ka, Tomoyuki Ogura, Hiroshi Suemizu, Yutaka Kawakami, Mamoru Ito

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22 Citations (Scopus)

Abstract

We generated a severe immunodeficient NOD/Shi-scid-IL-2Rγnull (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-CD56highCD16+/- 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.

Original languageEnglish
Pages (from-to)3513-3525
Number of pages13
JournalJournal of Immunology
Volume194
Issue number7
DOIs
Publication statusPublished - 2015 Apr 1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Katano, I., Takahashi, T., Ito, R., Kamisako, T., Mizusawa, T., Ka, Y., Ogura, T., Suemizu, H., Kawakami, Y., & Ito, M. (2015). Predominant development of mature and functional human NK cells in a novel human IL-2 - Producing transgenic NOG mouse. Journal of Immunology, 194(7), 3513-3525. https://doi.org/10.4049/jimmunol.1401323