DNAM-1 Activating Receptor and Its Ligands: How Do Viruses Affect the NK Cell-Mediated Immune Surveillance during the Various Phases of Infection?

Abstract

Natural Killer (NK) cells play a critical role in host defense against viral infections. The mechanisms of recognition and killing of virus-infected cells mediated by NK cells are still only partially defined. Several viruses induce, on the surface of target cells, the expression of molecules that are specifically recognized by NK cell-activating receptors. The main NK cell-activating receptors involved in the recognition and killing of virus-infected cells are NKG2D and DNAM-1. In particular, ligands for DNAM-1 are nectin/nectin-like molecules involved also in mechanisms allowing viral infection. Viruses adopt several immune evasion strategies, including those affecting NK cell-mediated immune surveillance, causing persistent viral infection and the development of virus-associated diseases. The virus's immune evasion efficacy depends on molecules differently expressed during the various phases of infection. In this review, we overview the molecular strategies adopted by viruses, specifically cytomegalovirus (CMV), human immunodeficiency virus (HIV-1), herpes virus (HSV), Epstein-Barr virus (EBV) and hepatitis C virus (HCV), aiming to evade NK cell-mediated surveillance, with a special focus on the modulation of DNAM-1 activating receptor and its ligands in various phases of the viral life cycle. The increasing understanding of mechanisms involved in the modulation of activating ligands, together with those mediating the viral immune evasion strategies, would provide critical tools leading to design novel NK cell-based immunotherapies aiming at viral infection control, thus improving cure strategies of virus-associated diseases.

Keywords: DNAM-1; NK cells; Nectin-2; PVR; activating ligands; immune surveillance; viral life cycle phases; viruses.

Figure 1

DNAM-1 signaling pathway leading to natural killer (NK) cell activation. (A) NK cell, not interacting with target cell, is not functional. FOXO1 negatively controls, at transcriptional level, many NK cell effector functions, including the cell homing and late-stage maturation. (B) When the immunological synapse is established between a NK cell and a target cell, several activating signal pathways trigger NK cell activation, including those mediated by DNAM-1. Upon the engagement of DNAM-1 with Nectin-2 or PVR activating ligands, expressed on the target cell, PKC phosphorylates the cytoplasmic domain of DNAM-1. At the same time ICAM-1, expressed on the target cell, binds LFA-1; thus promoting its conformational change; the recruitment of Fyn that phosphorylates the DNAM-1 cytoplasmic domain; and, as a consequence, the association of DNAM-1 with LFA-1. The DNAM-1 downstream signaling cascade leads to the phosphorylation of SLP-76 and Vav1, that induce the activation of PLCγ2 and, downstream, of ERK and AKT. This DNAM-1-dependent signaling cascade promotes the expression of genes involved in the degranulation and calcium (Ca²⁺) mobilization, leading to the NK cell activation. Activated AKT phosphorylates FOXO1, thus mediating the FOXO1 translocation from the nucleus to the cytoplasm, where it is degraded and inactivated. The expression of the immune checkpoint molecules TIGIT and CD96 renders NK cell functionally exhausted, since both receptors compete with DNAM-1 for the binding to the same activating ligands (indicated by black arrows).

Figure 2

Viruses differently modulate the expression of DNAM-1 and their ligands depending on the infection phase. The viruses mentioned in this review (CMV, HIV-1, HSV, EBV, and HCV) differently express proteins associated with the various viral infection phases. Viral proteins (blue boxes) can upregulate (green arrow) or downregulate (red inhibition symbol) the expression of DNAM-1 and its ligands, such as PVR and Nectin-2, as reported in the legend. The US2 protein of CMV supports the immunomodulating function of UL141 during viral infection (blue arrow). References relative to each mechanism are reported in parenthesis. General missing information are indicated by emoticons, while missing information on viral molecules are indicated by question marks.