Although NK cell differentiation leads to acquisition of function, little is known about how cell survival affects the NK cell repertoire. We found that Killer-cell immunoglobulin-like receptor positive (KIR+) NK cells, which exhibit enhanced cytotoxicity and cytokine production, survived better than KIR- NK cells under serum starving conditions. Accordingly, KIR+ NK cells have more anti-apoptotic proteins, while they express less Fas and FasL. As NK cell survival and homeostasis are mediated by cytokine signaling, we studied expression of IL-15 and IL-2 signaling components: the shared IL-2Rβ and the common γ chain, and the individual “private” components, IL-2Rα for IL-2 and IL-15Rα for IL-15. IL-2Rα was expressed at lower levels on KIR+ NK cells while the common γ chain was higher in these cells. Interestingly, IL-15 has been shown to induce survival signals better than IL-2. We hypothesized that IL-15Rα and IL-2Rα compete for common components to influence survival and tested this by overexpressing or knocking down IL-2Rα. IL-2Rα expression negatively influenced IL-15 mediated survival confirming our hypothesis. Since no crosslinking or IL-2 signals were present in this experiment, this role differs from that of IL-2 in AICD, supporting our competition mechanism. Finally, we found a direct correlation between NK cell education/licensing and enhanced survival. In the clinic these findings could lead to better NK cell persistence required for clinical efficacy.
- Copyright © 2013 by The American Association of Immunologists, Inc.