Mechanisms of superior ants-tumor cytotoxic response of interleukin 15-induced lymphokine-activated killer cells

Interleukin (IL) 15 is one of the main cytokines controlling cytotoxic lymphocyte survival and growth. Despite its receptor and functional similarity to IL-2, IL-15 affects a wider target cell population and utilizes different mechanisms in cell activation. The role of IL-15 in lymphokine-activated killer (LAK) cell generation in vitro and potential mechanisms of cytotoxicity compared with equivalent low concentration of IL-2 with or without mitogens (phytohemoglutinin (PHA) and anti-CD3 antibody) have been investigated in this study. IL-15 treatment resulted in moderate cell proliferation over 7 days, whereas IL-2 treatment was associated with decreased cell numbers. Unlike IL-2 in combination with mitogens, IL-15 caused increases in both cytotoxic T lymphocytes (CTL) and CD56⁺ LAK cells, particularly cytokine-induced killer and cytolytic natural killer T-cell (CNK-T) subpopulations, which are known to be highly effective in cytotoxicity. IL-15 also increased overall perform and tumor necrosis factor-α expression and more prominently in CTLs. Consequently, IL-15 resulted in superior cytotoxicity against two different NK-sensitive (human K-562 and murine YAC-1) and LAK-sensitive (human Daudi and Raji) cell lines compared with other cytokine combinations. There was also no contribution of mitogens to IL-2-induced cytotoxicity. In conclusion, IL-15 at the concentration of 10 ng/mL used in this study causes moderate proliferation and superior cytotoxicity of LAK cells in vitro that was associated with induction of a specific LAK cell subpopulation profile and related cellular killing mechanisms. These results are encouraging for potential use of IL-15 as part of immunotherapy.