A subpopulation of human peripheral blood NK cells that lacks inhibitory receptors for self-MHC is developmentally immature. Blood

Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis 55455, USA.
Blood (Impact Factor: 10.45). 08/2007; 110(2):578-86. DOI: 10.1182/blood-2006-07-036228
Source: PubMed


How receptor acquisition correlates with the functional maturation of natural killer (NK) cells is poorly understood. We used quantitative real-time polymerase chain reaction (PCR) assays to compare NKG2 and killer immunoglobulin-like receptor (KIR) gene expression in NK cells from allogeneic transplant recipients and their donors. Marked differences were observed in the NK subsets of recipients who had 8-fold more CD56(bright) cells, diminished KIR expression (except 2DL4), and increased NKG2A. In normal blood not all CD56(dim) cells express KIR, and a novel subpopulation of cells committed to the NK-cell lineage was defined. These cells, which comprise 19.4% +/- 2.8% of the CD56(dim) NK population in healthy donors, express the activating NKG2D and NKG2E receptors but no KIR or NKG2A. Although the CD56(dim) NKG2A(-) KIR(-) NK cells lack "at least one" inhibitory receptor for autologous MHC class I, they are not fully responsive, but rather functionally immature cells with poor cytotoxicity and IFN-gamma production. Upon culture with IL-15 and a stromal cell line, CD56(dim) and CD56(bright) KIR(-) NK cells proliferate, express KIR, and develop cytotoxicity and cytokine-producing potential. These findings have implications for the function of NK cells reconstituting after transplantation and support a model for in vivo development in which CD56(bright) cells precede CD56(dim) cells.

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    • "This results in mature and functional NK cells that are inhibited by germline encoded receptors that recognize self-MHC or related ligands and can effectively sense the loss of such self-ligands or increased expression of activating receptor ligands [25, 26]. A subset of CD56dim⁡ NK cells identified in humans, which fail to express KIR that recognize self-HLA ligands, was found to be hypofunctional, suggesting a lack of education and anergy [27]. "
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    ABSTRACT: Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy.
    06/2014; DOI:10.1155/2014/205796
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    • "In order to become fully competent NK cells have been shown to require recognition of self HLA class I molecules during maturation, a phenomenon referred to as “licensing” or “education” (30–32). However, unlicensed NK cells lacking inhibitory receptors specific for self HLA molecules (either KIR or NKG2A/CD94) do exist, but are hyporesponsive (31, 33). Thus, in a self environment the NK cell receptor repertoire will ensure self tolerance as each functional NK cell expresses at least one inhibitory receptor specific for self HLA-I molecules. "
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    ABSTRACT: Natural Killer (NK) cell function is regulated by an array of inhibitory and activating surface receptors that during NK cell differentiation, at variance with T and B cells, do not require genetic rearrangement. Importantly, NK cells are the first lymphocyte population recovering after hematopoietic stem cell transplantation (HSCT). Thus, their role in early immunity after HSCT is considered crucial, as they can importantly contribute to protect the host from tumor recurrence and viral infections before T-cell immunity is fully recovered. In order to acquire effector functions and regulatory receptors, NK cell precursors undergo a maturation process that can be analyzed during immune reconstitution after HSCT. In this context, the occurrence of human cytomegalovirus (HCMV) infection/reactivation was shown to accelerate NK cell maturation by promoting the differentiation of high frequencies of NK cells characterized by a KIR(+)NKG2A(-) and NKG2C(+) mature phenotype. Thus, it appears that the development of NK cells and the distribution of NK cell receptors can be deeply influenced by HCMV infection. Moreover, in HCMV-infected subjects the emergence of so called "memory-like" or "long-lived" NK cells has been documented. These cells could play an important role in protecting from infections and maybe from relapse in patients transplanted for leukemia. All the aspects regarding the influence of HCMV infection on NK cell development will be discussed.
    Frontiers in Immunology 12/2013; 4:458. DOI:10.3389/fimmu.2013.00458
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    • "The phenotypic maturation of NK cells following transplant appears to follow a specific pattern. Regulation of maturation can be mediated by the status of KIR ligand matching24, 25, infections16, 26, and cytokines13. Initially, an expansion of CD56bright cells has been described; these cells display an immature phenotype as evidenced by high expression of NKG2A/CD94 heterodimer27-29. "
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    ABSTRACT: Natural killer (NK) cells are one of the first cells to recover following allogeneic hematopoietic stem cell transplantation (HSCT), and are believed to play an important role in facilitating engraftment or preventing post-transplant infection and tumor recurrence. Recent studies have provided novel insights into the mechanisms by which NK cells mediate these highly clinically relevant immunological functions. In particular, the ability of NK cells to reduce the risk of graft versus host disease (GVHD) and increase the graft versus leukemia effect (GVL) in the setting of human leukocyte antigen (HLA)-haploidentical HSCT highlights their clinical potentials. NK cells also mediate anti-viral protection, in particular against cytomegalovirus (CMV), an infection that causes significant morbidity and mortality following transplant. Another crucial function of NK cells is providing protection against bacterial infections at the mucosal barriers. NK cells achieve this by promoting anti-microbial defenses and regeneration of epithelial cells. These recent exciting findings provide a strong basis for the formulation of novel NK cell-based immunotherapies. In this review, we summarize the recent advances related to the mechanisms, functions, and future clinical prospects of NK cells that can impact post-transplant outcomes.
    Journal of Cancer 02/2013; 4(1):25-35. DOI:10.7150/jca.5049 · 3.27 Impact Factor
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