Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30

Natural killer (NK) cells are part of the innate immunity repertoire, and function in the recognition and destruction of tumorigenic and pathogen-infected cells. Engagement of NK cell activating receptors can lead to functional activation of NK cells, resulting in lysis of target cells. NK cell activating receptors specific for non-major histocompatibility complex ligands are NKp46, NKp44, NKp30, NKG2D, and CD16 (also known as FcγRIII). The natural cytotoxicity receptors (NCRs), NKp46, NKp44, and NKp30, have been implicated in functional activation of NK cells following influenza virus infection via binding with influenza virus hemagglutinin (HA). In this review we describe NK cell and influenza A virus biology, and the interactions of influenza A virus HA and other pathogen lectins with NK cell natural cytotoxicity receptors (NCRs). We review concepts which intersect viral immunology, traditional virology and glycobiology to provide insights into the interactions between influenza virus HA and the NCRs. Furthermore, we provide expert opinion on future directions that would provide insights into currently unanswered questions.

Role of the Main Non HLA-Specific Activating NK Receptors in Pancreatic, Colorectal and Gastric Tumors Surveillance

Human NK cells can control tumor growth and metastatic spread thanks to their powerful cytolytic activity which relies on the expression of an array of activating receptors. Natural cytotoxicity receptors (NCRs) NKG2D and DNAM-1 are those non-HLA-specific activating NK receptors that are mainly involved in sensing tumor transformation by the recognition of different ligands, often stress-induced molecules, on the surface of cancer cells. Tumors display several mechanisms aimed at dampening/evading NK-mediated responses, a relevant fraction of which is based on the downregulation of the expression of activating receptors and/or their ligands. In this review, we summarize the role of the main non-HLA-specific activating NK receptors, NCRs, NKG2D and DNAM-1, in controlling tumor growth and metastatic spread in solid malignancies affecting the gastrointestinal tract with high incidence in the world population, i.e., pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and gastric cancer (GC), also describing the phenotypic and functional alterations induced on NK cells by their tumor microenvironment.

The Antitumor Effect of Heparin is not Mediated by Direct NK Cell Activation

Natural killer (NK) cells are innate lymphocytes responsible for the elimination of infected or transformed cells. The activation or inhibition of NK cells is determined by the balance of target cell ligand recognition by stimulatory and inhibitory receptors on their surface. Previous reports have suggested that the glycosaminoglycan heparin is a ligand for the natural cytotoxicity receptors NKp30, NKp44 (human), and NKp46 (both human and mouse). However, the effects of heparin on NK cell homeostasis and function remain unclear. Here, we show that heparin does not enhance NK cell proliferation or killing through NK cell activation. Alternatively, in mice models, heparin promoted NK cell survival in vitro and controlled B16-F10 melanoma metastasis development in vivo. In human NK cells, heparin promisingly increased interferon (IFN)-γ production in synergy with IL-12, although the mechanism remains elusive. Our data showed that heparin is not able to increase NK cell cytotoxicity.

Natural Cytotoxicity Receptors in Decidua Natural Killer Cells of Term Normal Pregnancy

Aim. To investigate the changes in the maternal immune system at term pregnancy, we studied the expression of natural cytotoxicity receptors (NCRs) and the cytokine production of NK cells in term placenta decidua and peripheral blood. Methods. Term decidua and peripheral blood were taken from patients undergoing elective cesarean section. The lymphocytes were separated using density gradient centrifugation (DGC) from peripheral blood and were separated from decidua using DGC after enzyme digestion. These cells were stained with FITC anti-CD56 and Per-CP anti-CD3 monoclonal antibodies, and the NCRs were stained with PE-conjugated anti-NKG2D, NKp46, NKp30, and NKp44 monoclonal antibodies. Cytokines, including IFN-γ, TNF-α, IL-10, and TGF-β, were stained and then analyzed by flow cytometry. Results. There were fewer cells positive for NKG2D, NKp46, and NKp30 among CD56+CD3- cells in deciduas than in peripheral blood, but the percentages of NKp44-positive cells in CD56+CD3- lymphocytes in deciduas tended to be higher. Conclusion. The decreased expression of some NCRs in deciduas may be related to decreased cytotoxicity at term pregnancy, but the increased expression of NKp44 may affect the increased cytokine production in the decidua. Similarly, the expression of NCRs in the decidua may be connected to the maintenance of pregnancy at term.

The Antitumor Immunity Mediated by NK Cells: The Role of The NCRs

Natural Killer (NK) cells are innate immune lymphocytes that are important for early and effective immune responses against infections and cancer. The antitumor immunity mediated by NK cells can be exerted through several direct or indirect “immunosurveillance” mechanisms that control tumor growth and prevent the rapid dissemination of metastatic tumors. NK cells express an array of activating and inhibitory receptors that enable them to recognize and bind non-self as well as self-ligands expressed on the surface of malignant or virally infected cells. The family of Natural Cytotoxicity Receptors (NCRs) comprises three activating receptors; NKp30, NKp44, and NKp46 that are important for the stimulation of NK cell effector functions. This review summarizes the mechanisms of antitumor immunity mediated by natural killer cells with focus on the role of the family of the NCRs and their tumor associated ligands.