Structural insights into activation of antiviral NK cell responses

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Immunological Reviews (Impact Factor: 10.12). 11/2012; 250(1):239-57. DOI: 10.1111/j.1600-065X.2012.01168.x
Source: PubMed


Natural killer (NK) cells are key components of innate immune responses, providing surveillance against cells undergoing tumorigenesis or infection, by viruses or internal pathogens. NK cells can directly eliminate compromised cells and regulate downstream responses of the innate and acquired immune systems through the release of immune modulators (cytokines, interferons). The importance of the role NK cells play in immune defense was demonstrated originally in herpes viral infections, usually mild or localized, which become severe and life threatening in NK-deficient patients . NK cell effector functions are governed by balancing opposing signals from a diverse array of activating and inhibitory receptors. Many NK receptors occur in paired activating and inhibitory isoforms and recognize major histocompatibility complex (MHC) class I proteins with varying degrees of peptide specificity. Structural studies have made considerable inroads into understanding the molecular mechanisms employed to broadly recognize multiple MHC ligands or specific pathogen-associated antigens and the strategies employed by viruses to thwart these defenses. Although many details of NK development, signaling, and integration remain mysterious, it is clear that NK receptors are key components of a system exquisitely tuned to sense any dysregulation in MHC class I expression, or the expression of certain viral antigens, resulting in the elimination of affected cells.

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    • "killer-cell immunoglobulin-like receptors and leukocyte inhibitory receptors) receptors that do not undergo rearrangement. These receptors recognize their cognate ligands on the surface of infected cells, and the complex interplay between them determines the activation of NK cells (Finton and Strong, 2012). The mechanisms by which NK cells execute their effector functions include cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC), production of cytokines, and modulation of DCs (Vivier, 2006; Münz et al., 2005; Inngjerdingen et al., 2011). "
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    ABSTRACT: Natural Killer (NK) cells constitute a major subset of innate lymphoid cells that do not express the T- and B-cell receptors and play an important role in antimicrobial defense. NK cells not only induce early and rapid innate immune responses, but also communicate with dendritic cells to shape the adaptive immunity, thus bridging innate and adaptive immunity. Although the functional biology of NK cells is well-documented in a variety of infections in humans and mice, their role in protecting domestic animals from infectious agents is only beginning to be understood. In this article, we summarize the current state of knowledge about the contribution of NK cells in pathogen defense in domestic animals, especially cattle and pigs. Understanding the immunobiology of NK cells will translate into strategies to manipulate these cells for preventive and therapeutic purposes.
    Veterinary Immunology and Immunopathology 10/2015; 168(1-2). DOI:10.1016/j.vetimm.2015.10.001 · 1.54 Impact Factor
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    • "Virus-infected cells often induce or increase the expression of ligands at their surface, allowing for recognition by NK cell activating receptors, including NKG2D, DNAM-1, CD94-NKG2C; the NCR receptors NKp46, NKp30, NKp44; and others (19, 20, 22). The ligands include host stress-induced molecules and viral proteins (20). "
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    ABSTRACT: The innate immune response, in addition to the B- and T-cell response, plays a role in protection against dengue virus (DENV) infection and the degree of disease severity. Early activation of natural killer (NK) cells and type-I interferon-dependent immunity may be important in limiting viral replication during the early stages of DENV infection and thus reducing subsequent pathogenesis. NK cells may also produce cytokines that reduce inflammation and tissue injury. On the other hand, NK cells are also capable of inducing liver injury at early-time points of DENV infection. In vitro, NK cells can kill antibody-coated DENV-infected cells through antibody-dependent cell-mediated cytotoxicity. In addition, NK cells may directly recognize DENV-infected cells through their activating receptors, although the increase in HLA class I expression may allow infected cells to escape the NK response. Recently, genome-wide association studies have shown an association between MICB and MICA, which encode ligands of the activating NK receptor NKG2D, and dengue disease outcome. This review focuses on recognition of DENV-infected cells by NK cells and on the regulation of expression of NK cell ligands by DENV.
    Frontiers in Immunology 05/2014; 5:192. DOI:10.3389/fimmu.2014.00192
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    • "NKp44 and NKp46 bind influenza and other viral hemagglutinins (HAs) mainly through recognition by the HA of terminal sialic acid moieties (the cellular receptor for HAs) on N-linked glycans of these NCRs (72, 76, 77). Although this mechanism would allow NKp44 and NKp46 to bind a wide variety of viruses, due to the ability of HAs to bind sialic acid-containing glycoproteins in general, this is probably not the full story, since recognition would not depend on the NCR ectodomain itself, but only on the fact that NKp44 and NKp46 are glycoproteins with terminal sialic acids (13). Binding of NKp46 to heparan sulfate proteoglycans has also been described (78), but the biological relevance of this interaction is unclear. "
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    ABSTRACT: Natural killer (NK) cells are key components of innate immune responses to tumors and viral infections. NK cell function is regulated by NK cell receptors that recognize both cellular and viral ligands, including major histocompatibility complex (MHC), MHC-like, and non-MHC molecules. These receptors include Ly49s, killer immunoglobulin-like receptors, leukocyte immunoglobulin-like receptors, and NKG2A/CD94, which bind MHC class I (MHC-I) molecules, and NKG2D, which binds MHC-I paralogs such as the stress-induced proteins MICA and ULBP. In addition, certain viruses have evolved MHC-like immunoevasins, such as UL18 and m157 from cytomegalovirus, that act as decoy ligands for NK receptors. A growing number of NK receptor-ligand interaction pairs involving non-MHC molecules have also been identified, including NKp30-B7-H6, killer cell lectin-like receptor G1-cadherin, and NKp80-AICL. Here, we describe crystal structures determined to date of NK cell receptors bound to MHC, MHC-related, and non-MHC ligands. Collectively, these structures reveal the diverse solutions that NK receptors have developed to recognize these molecules, thereby enabling the regulation of NK cytolytic activity by both host and viral ligands.
    Frontiers in Immunology 03/2014; 5:123. DOI:10.3389/fimmu.2014.00123
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