Cytokine activation induces CD25 expression and a functional high-affinity IL-2 receptor on CD56dim human NK Cells (P4349)

The heterotrimeric high affinity IL-2 receptor (IL-2Rαβγ) is expressed on CD56bright human NK cells and confers responsiveness to picomolar concentrations of IL-2. In contrast, resting CD56dim NK cells lack IL-2Rα (CD25), but constitutively express the intermediate affinity IL-2Rβγ chains. Here, we show that cytokine-activation induces rapid and prolonged expression of CD25 on CD56dim NK cells, especially the combination of IL-15 plus IL-18. This expression of CD25 correlated with STAT5 phosphorylation in response to picomolar concentrations of IL-2, indicating the presence of a signal-competent IL-2Rαβγ. Furthermore, picomolar concentrations of IL-2 acted synergistically with IL-12 to co-stimulate IFN-γ production by pre-activated CD56dim NK cells. Similarly, low dose IL-2 enhanced the cytotoxicity of pre-activated CD56dim NK cells against K562 tumor targets. Both effects were dependent on the expression of CD25. Preliminary experiments also suggest that the induction of CD25 on CD56dim NK cells enhances proliferative capacity and survival in cultures supplemented with low dose IL-2. Since CD56dim NK cells represent the major subset of human peripheral blood NK cells, these data support a rationale for immunotherapeutic strategies that include cytokine pre-activation prior to adoptive NK cell transfer, followed by low dose IL-2 therapy.