Functional NK Cell Repertoires Are Maintained through IL-2Ra and Fas Ligand

Acquisition of a functional NK cell repertoire, known as education or licensing, is a complex process mediated through inhibitory receptors that recognize self. We found that NK cells containing self-killer Ig-like receptors for cognate HLA ligand in vivo were less susceptible to apoptosis. In vitro IL-15 withdrawal showed that uneducated NK cells upregulated Bim and Fas. Conversely, educated NK cells upregulated Fas ligand (FasL) under these conditions. Induction of cell death and Bim expression on uneducated cells correlated with increased IL-2Ra expression. Overexpression and knockdown studies showed that higher IL-2Ra limits NK cell survival in a novel manner that is independent from the role of IL-2 in activation-induced cell death. To study the role of FasL in induction of IL-2Ra hi NK cell death, a coculture assay with FasL-blocking Abs was used. IL-15 withdrawal led to FasL-dependent killing of IL-2Ra hi NK cells by more educated IL-2Ra lo NK cells. Finally, CMV reactivation induces a potent long-lasting population of licensed NK cells with enhanced survival. These findings show that education-dependent NK cell survival advantages and killing of uneducated NK cells result in the maintenance of a functional repertoire, which may be manipulated to exploit NK cells for cancer immunotherapy. N atural killer cell–mediated immunotherapy is being tested in clinical trials (1, 2). Inhibitory killer Ig-like receptors (KIRs) on NK cells induce function through a process termed " education " or " licensing " (3–5). The success of NK cell therapy depends on how functionally competent cells are home-ostatically maintained after adoptive transfer. Although NK cell homeostasis has been studied on bulk NK cells, questions remain as to how the repertoire of functionally competent NK cells is maintained to exploit its differentiation state and previous exposure history (6–9). The balance between more mature KIR + NK cells and less differentiated KIR 2 NK cells could be regulated by three mechanisms in the periphery: proliferation, differentiation, and survival. Higher proliferation in the KIR 2 NK cell subset (10) and poor proliferation of more mature CD57 + NK cells have been described (11). These data suggest that the differentiation status of NK cells correlates inversely with proliferative potential. Differentiation could explain the persistence of KIR + NK cells that develop from KIR 2 NK cells. Alternatively, it was shown that KIR expression on T cells may inhibit activation-induced cell death (AICD) by inducing PI3K/Akt (12–15), suggesting that enhanced survival could control the balance …