Natural killer cell education results in prolonged survival through a cytokine receptor balance mediated mechanism (P1435)

Abstract

Abstract 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.