SUMMARY The mechanisms underlying human natural killer (NK) cell phenotypic and functional heterogeneity are unknown. Here, we describe the emergence of diverse subsets of human NK cells selectively lacking expression of signaling proteins after human cytomegalovirus (HCMV) infection. The absence of B and myeloid cell-related signaling protein expression in these NK cell subsets correlated with promoter DNA hyperme-thylation. Genome-wide DNA methylation patterns were strikingly similar between HCMV-associated adaptive NK cells and cytotoxic effector T cells but differed from those of canonical NK cells. Functional interrogation demonstrated altered cytokine responsiveness in adaptive NK cells that was linked to reduced expression of the transcription factor PLZF. Furthermore, subsets of adaptive NK cells demonstrated significantly reduced functional responses to activated autologous T cells. The present results uncover a spectrum of epigenetically unique adaptive NK cell subsets that diversify in response to viral infection and have distinct functional capabilities compared to canonical NK cell subsets.

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Objective. To determine the phenotype and the functionality of natural killer (NK) cells in patients with systemic lupus erythematosus (SLE).Methods. A total of 94 patients with SLE (91 women and 3 men) were compared with 26 healthy controls. Active SLE was defined by an SLE Disease Activity Index score >4. Immunologic tests were performed using nonactivated and/or interleukin-2 (IL-2)-activated peripheral blood mononuclear cells. NK cell phenotype was determined by flow cytometry. NK cell natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) were determined by 51 Cr release and CD107a degranulation experiments. Intracellular interferon-␥ (IFN␥) production by NK cells was evaluated after overnight stimulation with IL-12 and IL-18. IFN␣ levels were assessed using an antiviral cytopathic bioassay.Results. The absolute NK cell count was decreased in patients with active SLE, but the relative frequencies of total CD3؊CD56 bright NK cells and CD3؊CD56 dim NK cells were unaffected. The Natural killer (NK) cells provide the first line of defense against infections and developing malignancies. They are a heterogeneous subset of cells that differ in their proliferative potential, homing characteristics, functional capacities, and responses to different cytokines. They can be divided into 2 major subsets, based on the relative densities of CD56 surface expression. Peripheral blood NK cells comprise ϳ10% CD56 bright and ϳ90% CD56 dim NK cell subsets, which are relatively distinct upon activation (1). CD56 bright NK cells proliferate and produce a wide range of cytokines (e.g., interferon-␥ [IFN␥], tumor necrosis factor ␤, and interleukin-10 [IL-10]) and chemokines (e.g., macrophage inflammatory protein 1␣ and RANTES) but display minimal cytotoxic activity, while CD56 dim NK

Natural killer (NK) cells generated after haploidentical hematopoietic SCT in patients with AML are characterized by specific phenotypic features and impaired functioning that may affect transplantation outcome. We show that IFN-c produced by immature CD56 bright NK cells upregulates cell surface expression of HLA-E on AML blasts and that this upregulation protects leukemic cells from NK-mediated cell lysis through the mediation of CD94/NKG2A, an inhibitory receptor overexpressed on NK cells after haploidentical SCT. Two years after transplantation, however, maturing NK cells were functionally active, as evidenced by high cytotoxicity and poor IFN-c production. This implies that maturation of NK cells is the key to improved immune responses and transplantation outcome.