Effect of exposure to interleukin-21 at various time points on human natural killer cell culture

Cytotherapy. 2014 Oct;16(10):1419-30. doi: 10.1016/j.jcyt.2014.04.008. Epub 2014 Jun 18.

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.

Keywords: IL-15; IL-2; IL-21; natural killer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Flow Cytometry
  • Humans
  • Interferon-gamma / metabolism
  • Interleukin-15 / pharmacology
  • Interleukin-2 / pharmacology
  • Interleukins / pharmacology*
  • K562 Cells
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology
  • Perforin / metabolism
  • Telomere Homeostasis / drug effects
  • Telomere Homeostasis / immunology
  • Time Factors

Substances

  • Interleukin-15
  • Interleukin-2
  • Interleukins
  • Perforin
  • Interferon-gamma
  • interleukin-21