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Mouse Producing Transgenic NOG − Human IL-2 Functional Human NK Cells in a Novel Predominant Development of Mature

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Mouse Producing Transgenic NOG − Human IL-2 Functional Human NK Cells in a Novel Predominant Development of Mature Predominant Development of Mature and Functional Human NK Cells in a Novel Human IL-2−Producing Transgenic NOG Mouse This information is current as of October 2, 2021. Ikumi Katano, Takeshi Takahashi, Ryoji Ito, Tsutomu Kamisako, Takuma Mizusawa, Yuyo Ka, Tomoyuki Ogura, Hiroshi Suemizu, Yutaka Kawakami and Mamoru Ito J Immunol published online 23 February 2015 http://www.jimmunol.org/content/early/2015/02/21/jimmun Downloaded from ol.1401323 Supplementary http://www.jimmunol.org/content/suppl/2015/02/21/jimmunol.140132 Material 3.DCSupplemental http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published February 23, 2015, doi:10.4049/jimmunol.1401323 The Journal of Immunology 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,† and Mamoru Ito* We generated a severe immunodeficient NOD/Shi-scid-IL-2Rgnull (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), CD32CD56highCD16+/2 cells developed unexpectedly, predominantly in the NOG–IL-2 Tg (hu-HSC NOG–IL-2 Tg). These cells expressed various NK recep- tors, including NKp30, NKp44, NKp46, NKG2D, and CD94, as well as a diverse set of killer cell Ig-like receptor molecules at levels Downloaded from 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-g 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2015, 194: 000–000. atural killer cells are members of the innate lymphoid cell These cells engage in the clearance of viral pathogens or intra- family (1). These cells make up 5–20% of lymphocytes cellular microbes as the first line of defense. Because of their in normal human peripheral blood (PB) and are dis- potent tumor-killing activity, NK cells are considered critical in N by guest on October 2, 2021 tributed in various organs, including the liver, lung, spleen, and tumor immunosurveillance. Indeed, the induction of Ab-dependent lymph nodes. They are large granular lymphocytes and store cell cytotoxicity (ADCC) (2) in NK cells by therapeutic mAbs has perforin, granzymes, or IFN-g in their intracellular granules, become a mainstream form of cancer treatment (e.g., rituximab which they release in response to various immunological stimuli. [anti-CD20 mAb], trastuzumab [anti-Her2 mAb], and mogamuli- zumab [anti-CCR4 mAb]). Although applications of NK cells have increased in line with the *Central Institute for Experimental Animals, Kawasaki-ku, Kawasaki 210-0821, development of new mAbs, studies of human NK cells remain Japan; and †Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan largely dependent on in vitro systems. Usually, human NK cells are isolated from healthy donors or are induced from CD34+ hema- Received for publication May 22, 2014. Accepted for publication January 21, 2015. topoietic stem cells (HSCs) in the presence of cytokines. These This work was supported by Grant-in-Aid for Scientific Research (S) 22220007 (to M.I.) and Grant-in-Aid for Young Scientists 25871075 from the Ministry of Educa- cells are subsequently used to assay cytotoxicity or cytokine- tion, Culture, Sports, Science and Technology (MEXT), Japan. Japanese cord blood– producing ability in vitro. Despite their ease of use, in vitro sys- + derived CD34 stem cells were provided by RIKEN BioResource Center through the tems do not always provide sufficient information about the National Bio-Resource Project of MEXT, Japan (MTA CM00134). in vivo behavior of human NK cells, which is essential to under- I.K. performed all of the animal experiments and analyzed the data. I.K., T.T., R.I., and M.I. designed the study. Y. Kawakami advised on immunology. T.K. performed stand the interactions between human NK cells and their target embryo manipulation. T.M., Y. Ka, and T.O. bred NOG–IL-2 Tg mice. H.S. super- cells, such as tumor cells. Therefore, it is necessary to develop vised the genotyping of the Tg mice. M.I. organized the project. I.K., T.T., and M.I. novel in vivo experimental systems to study human NK cells. Such wrote the manuscript. systems must fulfill several requirements: long-term survival of Address correspondence and reprint requests to Dr. Takeshi Takahashi, Central In- stitute for Experimental Animals, 3-25-12 Tono-machi, Kawasaki-ku, Kawasaki 210- a significant number of human NK cells, maintenance of their 0821, Japan. E-mail address: [email protected] function, and the systems must be autonomous (i.e., not require The online version of this article contains supplemental material. exogenous manipulation or supplementation). Abbreviations used in this article: ADCC, Ab-dependent cell cytotoxicity; BM, bone Recent progress in the development of extremely severe im- 2 2 2 2 marrow; BRG, BALB/C-RAG2 / -IL-2Rgc / ; CB, cord blood; hPBMC, human munodeficient mouse strains has markedly improved engraftment PBMC; HSC, hematopoietic stem cell; iNK, immature NK; KIR, killer cell Ig-like receptor; MNC, mononuclear cell; NCR, natural cytotoxicity receptor; NKG2C, NK of xenotransplants. This humanized mouse technology has been group 2 membrane C; NOG, NOD/Shi-scid-IL-2Rgnull; NOG–IL-2 Tg, NOG mouse used to transfer human NK cells into immunodeficient mice to substrain expressing transgenic human IL-2; non-Tg, nontransgenic; PB, peripheral examine the cells’ in vivo cytotoxicity against tumors (3). The blood; PB-NK, PB-derived NK; qPCR, quantitative PCR. in vivo development of human NK cells from human HSCs also Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 was reported (4–6). However, the former approach was limited to www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401323 2 NK CELL DEVELOPMENT IN HUMANIZED NOG–IL-2 Tg MICE short-term experiments because of the rapid disappearance of the PB were prepared by density centrifugation on Ficoll (Lymphoprep; Axis- + human NK cells (3). Although the latter is more suitable for long- Shield, Oslo, Norway). Human CD56 NK cells were negatively selected term observation, the number of human NK cells was not always from hPBMCs or splenocytes of HSC-transferred mice between 4 and 6 wk post-HSC transplantation. Using a human NK cell isolation kit sufficient (4, 6), and exogenous administration of human IL-15 (Miltenyi Biotec, Bergisch Gladbach, Germany) in combination with bio- was needed to increase the population (5, 7). tin-conjugated anti-mouse CD45 mAb (BD Biosciences), all cells, with the In the course of modifying the NOD/Shi-scid-IL-2Rgnull (NOG) exception of human CD56+ NK cells, were magnetically labeled and mouse to produce the next generation of humanized mice (8–10), eliminated using a MACS LD column (Miltenyi Biotec). The purity of the isolated human NK cells was usually .90%. we established a NOG mouse substrain expressing human IL-2 In some experiments, we used commercially available white human NK (NOG–IL-2 Tg). In this study, we used this novel mouse strain as cells (AllCells, San Diego, CA). a recipient for HSCs; this resulted in unexpected differentiation of predominantly human NK cells in these mice. These human NK Flow cytometry cells were killer cell Ig-like receptor (KIR)-expressing mature cells The single MNC suspensions were stained with appropriate Abs for 30 min and showed the IL-2–activated phenotype. In addition, they at 4˚C in the dark. After washing with FACS buffer (PBS, 1% FBS, 0.1% strongly inhibited in vivo tumor formation. The NOG–IL-2 Tg will NaN3), the cells were resuspended in FACS buffer containing propidium iodide. We used a FACSCanto (BD Biosciences) for multicolor flow cyto- become a suitable platform for studying human NK cells in vivo.
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