Identification of PVR (CD155) and Nectin-2 (CD112) as Cell Surface Ligands for the Human DNAM-1 (CD226) Activating Molecule

By C. Bottino, R. Castriconi, D. Pende, Paola Rivera, M. Nanni, B. Carnemolla, C. Cantoni, J. Grassi, S. Marcenaro, Nicolas Reymond and 4 more. Journal of Experimental Medicine, 2003

887 citations recorded by the source corpus.

Human natural killer (NK) cells express a series of activating receptors and coreceptors that are involved in recognition and killing of target cells. In this study, in an attempt to identify the cellular ligands for such triggering surface molecules, mice were immunized with NK-susceptible target cells. On the basis of a functional screening, four mAbs were selected that induced a partial down-regulation of the NK-mediated cytotoxicity against the immunizing target cells. As revealed by biochemical analysis, three of such mAbs recognized molecules of ∼70 kD. The other mAb reacted with two distinct molecules of ∼65 and 60 kD, respectively. Protein purification followed by tryptic digestion and mass spectra analysis, allowed the identification of the 70 kD and the 65/60 kD molecules as PVR (CD155) and Nectin-2 δ/α (CD112), respectively. PVR-Fc and Nectin-2-Fc soluble hybrid molecules brightly stained COS-7 cells transfected with the DNAM-1 (CD226) construct, thus providing direct evidence that both PVR and Nectin-2 represent specific ligands for the DNAM-1 triggering receptor. Finally, the surface expression of PVR or Nectin-2 in cell transfectants resulted in DNAM-1–dependent enhancement of NK-mediated lysis of these target cells. This lysis was inhibited or even virtually abrogated upon mAb-mediated masking of DNAM-1 (on NK cells) or PVR or Nectin-2 ligands (on cell transfectants).

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/345ac42d0e52c91a77d5580e704f868347d998f3

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In Immunology

1. L. Moretta
2. A. Anderson
3. A. Moretta
4. V. Kuchroo
5. M. Peterson
6. D. Thommen
7. D. Blaise
8. A. Steinle

Citations in the corpus

• Controlling NK Cell Responses: Integration of Signals for Activation and Inhibition (2013, background): “DNAM-1 binds to the poliovirus receptor CD155 and the nectin adhesion molecule CD112 (67), both of which are upregulated on tumor cells.”
• TIGIT and PD-1 impair tumor antigen-specific CD8⁺ T cells in melanoma patients. (2015, positive): “CD155 and CD112 play a role in T cell– and NK cell–mediated cytotoxicity against tumors (21, 22).”
• Unravelling natural killer cell function: triggering and inhibitory human NK receptors (2004, background): “By contrast, most B-EBV cell lines analyzed do not express either PVR or Nectin-2, and their lysis does not involve DNAM-1 (Bottino et al, 2003).”
• NK cells and cancer immunosurveillance (2008, background): “…to adhesion molecules poliovirus receptor (PVR/CD155) and Nectin-2 (CD112) which also are IgSF members and broadly are expressed both by ‘healthy’ and malignant cells of epithelial and hematopoetic origin (Bottino et al., 2003; Pende et al., 2005; Carlsten et al., 2007; El Sherbiny et al., 2007).”
• T Cell Dysfunction in Cancer (2018, background): “Bottino C, Castriconi R, Pende D, Rivera P, Nanni M, Carnemolla B, Cantoni C, Grassi J, Marcenaro S, Reymond N, et al. Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule.”
• Lag-3, Tim-3, and TIGIT co-inhibitory receptors with specialized functions in immune regulation (2016, background): “CD226 (DNAM-1) and CD96 (Tactile) bind to the same ligands and together with TIGIT form a pathway in which CD226 delivers a positive co-stimulatory signal (Bottino et al., 2003), while CD96 and TIGIT deliver inhibitory signals (Figure 1C; Chan et al.”
• TIGIT in cancer immunotherapy (2020, background): “8 TIGIT participates in a complex regulatory network involving multiple IRs (eg, CD96/TACTILE, CD112R/PVRIG), one competing costimulatory receptor (DNAM-1/CD226), and multiple ligands (eg, CD155 (PVR/NECL-5), CD112 (Nectin-2/ PVRL2) 8 9 11–13 , figure 1).”
• Targeting natural killer cells and natural killer T cells in cancer (2012, background): “These receptors include DNAM1 (DNAX accessory molecule 1; also known as CD226) — which is activated by its ligands poliovirus receptor (PVR) and nectin 2 (also known as PVRL2”
• The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity (2009, background): “Fuchs A, Cella M, Giurisato E, Shaw AS, Colonna M (2004) Cutting edge: CD96 (tactile) promotes NK cell-target cell adhesion by interacting with the poliovirus receptor (CD155).”
• The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy (2017, background): “DNAM-1 recognizes CD155 (also known as Poliovirus receptor or PVR) and CD112 (Nectin-2) on tumor cells and induces NK cell-mediated lysis (80).”
• Activation, coactivation, and costimulation of resting human natural killer cells (2006, background): “DNAM-1 is associated with LFA-1 in NK cells (80), is phosphorylated by a protein kinase C (PKC) (81), and binds to polyoma virus receptor (PVR) (CD155) and nectin-2 (CD112) (82).”