Journal
CYTOTHERAPY
Volume 16, Issue 10, Pages 1419-1430Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.jcyt.2014.04.008
Keywords
IL-2; IL-15; IL-21; natural killer cells
Categories
Funding
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2010-0023757]
- Chonnam National University Hospital Research Institute of Clinical Medicine [CRI11081-21]
- National Research Foundation of Korea [2010-0023757] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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-gamma, 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.
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