Dong-Pyo Lim1, Youn-Young Jang2, Seokho Kim3, Sang Seok Koh3, Je-Jung Lee2, Ju-Sun Kim4, Minh-Trang Thi Phan5, Dong-Jun Shin6, Myung-Geun Shin7, Seung-Hwan Lee8, Meesun Yoon9, Sang-Ki Kim4, Jung-Han Yoon1, Min-Ho Park10, Duck Cho11. 1. Department of Surgery, Chonnam National University Medical School, Gwangju, Korea. 2. Research Center for Cancer Immunotherapy, Chonnam National University, Hwasun Hospital, Jeollanam-do, Korea. 3. Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea. 4. Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Korea. 5. Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea; Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Korea. 6. Research Center for Cancer Immunotherapy, Chonnam National University, Hwasun Hospital, Jeollanam-do, Korea; Department of Companion & Laboratory Animal Science, Kongju National University, Yesan, Korea. 7. Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea. 8. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada. 9. Department of Radiation Oncology, Chonnam National University Medical School, Gwangju, Korea. 10. Department of Surgery, Chonnam National University Medical School, Gwangju, Korea. Electronic address: mhpark@chonnam.ac.kr. 11. Research Center for Cancer Immunotherapy, Chonnam National University, Hwasun Hospital, Jeollanam-do, Korea; Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju, Korea; Center for Creative Biomedical Scientists at Chonnam National University, Gwangju, Korea. Electronic address: dcho@chonnam.ac.kr.
Abstract
BACKGROUND AIMS: Interleukin-21 (IL-21) can enhance the effector function of natural killer (NK) cells but also limits their proliferation when continuously combined with IL-2/IL-15. Paradoxically, membrane-bound (mb)-IL-21 has been shown to improve human NK cell proliferation when cultured with IL-2/mb-IL-15. To clarify the role of IL-21, we investigated the effect of the timing of IL-21 addition to NK cell culture. METHODS: IL-2/IL-15-activated NK cells were additionally treated with IL-21 according to the following schedules; (i) control (without IL-21); (ii) first week (day 0 to day 7); (iii) intermittent (the first 3 days of each week for 7 weeks); (iv) after 1 week (day 8 to day 14); and (v) continuous (day 0 to day 49). The expression of NK receptors, granzyme B, perforin, CD107a, interferon-γ, telomere length and NK cell death were measured by flow cytometry. RESULTS: Compared with the control (2004.2-fold; n = 10 healthy donors) and intermittent groups (2063.9-fold), a strong proliferative response of the NK cells on day 42 was identified in the "first week" group (3743.8-fold) (P < 0.05). NK cells treated with IL-21 in the "first week" group showed cytotoxicity similar to that in control cells. On day 28, there was a significant increase in cytotoxicity of "first week" NK cells that received IL-21 treatment for an additional 2 days compared with the "first week" NK cells (P < 0.05). CONCLUSIONS: These data suggest that controlling temporal exposure of IL-21 during NK cell proliferation can be a critical consideration to improve the yields and cytotoxicity of NK cells.
BACKGROUND AIMS: Interleukin-21 (IL-21) can enhance the effector function of natural killer (NK) cells but also limits their proliferation when continuously combined with IL-2/IL-15. Paradoxically, membrane-bound (mb)-IL-21 has been shown to improve human NK cell proliferation when cultured with IL-2/mb-IL-15. To clarify the role of IL-21, we investigated the effect of the timing of IL-21 addition to NK cell culture. METHODS:IL-2/IL-15-activated NK cells were additionally treated with IL-21 according to the following schedules; (i) control (without IL-21); (ii) first week (day 0 to day 7); (iii) intermittent (the first 3 days of each week for 7 weeks); (iv) after 1 week (day 8 to day 14); and (v) continuous (day 0 to day 49). The expression of NK receptors, granzyme B, perforin, CD107a, interferon-γ, telomere length and NK cell death were measured by flow cytometry. RESULTS: Compared with the control (2004.2-fold; n = 10 healthy donors) and intermittent groups (2063.9-fold), a strong proliferative response of the NK cells on day 42 was identified in the "first week" group (3743.8-fold) (P < 0.05). NK cells treated with IL-21 in the "first week" group showed cytotoxicity similar to that in control cells. On day 28, there was a significant increase in cytotoxicity of "first week" NK cells that received IL-21 treatment for an additional 2 days compared with the "first week" NK cells (P < 0.05). CONCLUSIONS: These data suggest that controlling temporal exposure of IL-21 during NK cell proliferation can be a critical consideration to improve the yields and cytotoxicity of NK cells.
Authors: Lisa L Liu; Aline Pfefferle; Vincent Oei Yi Sheng; Andreas T Björklund; Vivien Béziat; Jodie P Goodridge; Karl-Johan Malmberg Journal: Mol Oncol Date: 2015-10-20 Impact factor: 6.603
Authors: Polina A Kobyzeva; Maria A Streltsova; Sofya A Erokhina; Leonid M Kanevskiy; William G Telford; Alexander M Sapozhnikov; Elena I Kovalenko Journal: J Leukoc Biol Date: 2020-09-15 Impact factor: 6.011
Authors: Juliane Wagner; Viktoria Pfannenstiel; Anja Waldmann; Judith W J Bergs; Boris Brill; Sabine Huenecke; Thomas Klingebiel; Franz Rödel; Christian J Buchholz; Winfried S Wels; Peter Bader; Evelyn Ullrich Journal: Front Immunol Date: 2017-06-12 Impact factor: 7.561