Cumulative data from the relative fold difference in MitoTracker staining between vectors are shown (right). lineage of lymphocytes that function at the interface between innate and adaptive immunity (Vivier et al., 2011). They are important mediators of immunosurveillance and can eradicate susceptible infected and neoplastic cells through the targeted release of cytotoxic granules (K?gi et al., 1994). Recent studies of murine CMV contamination have exhibited that distinct subsets of NK cells can expand Phenethyl alcohol and persist long-term. These NK cells display hallmark features of adaptive T and B cells, including heightened effector functions and strong recall responses relative to nonadaptive subsets (Sun et al., 2009). In both mice and humans, adaptive NK cell growth is associated with improved antiviral and antitumor activity (Cichocki et al., 2016; Nabekura and Lanier, 2016; Redondo-Pachn et al., 2017). In humans, we as well as others have reported on unique subsets of human CMV (HCMV)Cassociated NK cells with a genome-wide DNA methylation profile comparable to that of effector CD8+ T cells. These adaptive NK cells display DNA methylationCdependent silencing of the transcription factor promyelocytic leukemia zinc finger and stochastic silencing of genes encoding the membrane proximal signaling molecules FcR, SYK, and/or EAT-2 (Lee et al., 2015; Schlums et al., 2015). Adaptive NK cell populations expressing the activating receptor NKG2C expand and persist in response to HCMV contamination in healthy donors (Gum et al., 2004) and HCMV reactivation in hematopoietic cell transplant (HCT) recipients (Foley et al., 2012). The majority of NKG2C+ NK cells in the peripheral blood of HCMV-seropositive individuals coexpress the Phenethyl alcohol maturation marker CD57 (Lopez-Vergs et al., 2011). Thus, HCMV contamination drives a remarkable degree of heterogeneity within the NK cell populace. Whether adaptive NK cells can be considered true memory lymphocytes in the same regard as T and B cells, or whether they represent a type of trained innate immunity described for monocyte-to-macrophage differentiation (Saeed et al., 2014), is still a matter of debate. Mounting evidence suggests that adaptive NK cell subsets have a survival and/or self-renewal advantage over canonical NK cells. Adaptive NK cells that expand in response to HCMV reactivation in HCT recipients are stable at high frequencies out to at least 2 yr after transplant (Foley et al., 2012; Cichocki et al., 2016), and epigenetically unique populations of adaptive NK cells in healthy HCMV-seropositive donors appear to persist at stable frequencies for at least 35 mo (Lee et al., 2015; Schlums et al., 2015). Further evidence for enhanced persistence/survival of adaptive NK cells comes from analysis of patients with paroxysmal nocturnal hemoglobinuria, in which adaptive NK cells typically represent a lineage that predates the acquired hematopoietic stem cell mutations that progressively dominate hematopoiesis and production of canonical NK cells (Corat et al., 2017). Moreover, adaptive NK cells persist in the peripheral blood of patients with heterozygous mutations, where constitutive differentiation of progenitor and canonical NK cells is usually lost (Schlums et al., 2017). The mechanistic Phenethyl alcohol basis for enhanced adaptive NK cell persistence is usually unclear. In particular, little is known regarding the metabolic attributes associated with adaptive NK cells that arise in response to HCMV contamination. Bioenergetic profiling of T cells has revealed that memory CD8+ T Rabbit polyclonal to AMACR cell metabolism is characterized by increased utilization of oxidative phosphorylation (OXPHOS), an oxygen-dependent process that maximizes the amount of ATP that can be derived from substrates. Memory T cells also exhibit a characteristic increase in mitochondrial mass, which is associated with higher spare respiratory capacity (SRC) relative to naive or effector T cell populations (van der Windt et al., 2012, 2013). Here, we show that adaptive NK cells from HCMV-seropositive individuals exhibit enhanced oxidative and glycolytic metabolic profiles relative to canonical NK cells. Adaptive NK cells also had increased mitochondrial membrane potential and higher expression of multiple genes encoding components of the mitochondrial ATP synthase complex and electron transport chain (ETC) relative to canonical NK cells. Mechanistically, we show that adaptive NK cells express elevated levels of the chromatin-modifying protein AT-rich interaction domain name 5B (ARID5B). Knockdown of ARID5B in an NK cell line (NK-92) led to decreases in mitochondrial oxidative metabolism, expression of ETC genes, survival, and IFN- production. Conversely, overexpression of ARID5B in NK-92 cells.