A Programmed Switch from IL-15- to IL-2-Dependent Activation in Human NK Cells (original) (raw)

2009, The Journal of Immunology

IL-2 and IL-15 differentially control the development, activation and proliferation of human NK cells, although they share common signal-transducing receptor chains CD122 and common ␥. To explore this issue, we analyzed in detail the kinetics of cytokine receptor expression, cytokine binding, and signaling responses in human NK cells treated with common ␥-chain family cytokines. We provide evidence for the sequential expression of IL-15R␣ and IL-2R␣ at the surface of cytokine-stimulated human NK cells, independent of the cytokine used for stimulation (IL-2, IL-15, or IL-7). Binding experiments confirmed the switch of high-affinity receptor from IL-15R to IL-2R between 18 and 48 h after stimulation. Consequently, phospho-STAT5 signaling responses to IL-15 were efficient in human NK cells pretreated with cytokines for 18 h, but were abolished at 48 h. Functional NK cell responses to IL-15, including IFN-␥ secretion and CD107a expression, followed a similar pattern, indicating the physiological relevance of the cytokine receptor switch. Importantly, IL-15 complexed to soluble IL-15R␣ preserved the capacity to activate cytokine-stimulated human NK cells at 48 h, suggesting that human NK cells remained competent for IL-15 trans-presentation, while they had become refractory to free diffusible IL-15. These findings define a common cytokine receptor expression program, which increases human NK cell sensitivity to free IL-15 in early activation and redirects responses toward IL-2 and trans-presented IL-15 at later stages. Such a program may prevent excessive human NK cell activation by effectors of innate immunity and regulate the transition between the innate and adaptive stages of immune responses.