Mechanisms governing human memory-like natural killer cell function.

Abstract

Abstract Natural killer (NK) cells are innate lymphoid cells critical for host defense against viral infection and malignant transformation. NK cells exhibit innate immunologic memory in response to specific haptens, viruses, or combined cytokine pre-activation. Human cytokine-induced memory-like NK cells, generated by overnight pre-activation with IL-12, IL-15, and IL-18, respond more robustly to numerous stimuli (including leukemia target cells) for weeks to months following the initial activation. The mechanisms responsible for the enhanced effector function of human memory-like NK cells are poorly understood. We hypothesized that memory-like NK cell differentiation alters the balance of signal integration downstream of activating and inhibitory receptors. NK cells achieve functional competence through self-MHC class I interactions (licensing) during maturation; if this does not occur, NK cells remain anergic. We tested this hypothesis using normal donors with licensed and unlicensed NK cell populations. We observed that cytokine pre-activation increases IFN-γ production by both licensed and unlicensed NK cells in response to tumor targets, activating receptor (FcγRIIIa) ligation, or cytokine stimulation. In fact, in response to cytokine stimulation, memory-like NK cells produce significantly more IFN-γ than controls with no impact of licensing. We observed no difference in the expression level of several signaling adaptor molecules or in phospho-signaling downstream of FcγRIIIa ligation in memory-like vs. control NK cells. We are currently investigating epigenetic modification of the IFN-γ gene locus in memory-like NK cells as a potential mechanism for their enhanced function; updated results will be presented.