Interaction between nectin-1 and the human natural killer cell receptor CD96

Abstract

Regulation of Natural Killer (NK) cell activity is achieved by the integration of both activating and inhibitory signals acquired at the immunological synapse with potential target cells. NK cells express paired receptors from the immunoglobulin family which share common ligands from the nectin family of adhesion molecules. The activating receptor CD226 (DNAM-1) binds to nectin-2 and CD155, which are also recognized by the inhibitory receptor TIGIT. The third receptor in this family is CD96, which is less well characterized and may have different functions in human and mouse models. Human CD96 interacts with CD155 and ligation of this receptor activates NK cells, while in mice the presence of CD96 correlates with decreased NK cell activation. Mouse CD96 also binds nectin-1, but the effect of this interaction has not yet been determined. Here we show that human nectin-1 directly interacts with CD96 in vitro . The binding site for CD96 is located on the nectin-1 V-domain, which comprises a canonical interface that is shared by nectins to promote cell adhesion. The affinity of nectin-1 for CD96 is lower than for other nectins such as nectin-3 and nectin-1 itself. However, the affinity of nectin-1 for CD96 is similar to its affinity for herpes simplex virus glycoprotein D (HSV gD), which binds the nectin-1 V-domain during virus entry. The affinity of human CD96 for nectin-1 is lower than for its known activating ligand CD155. We also found that human erythroleukemia K562 cells, which are commonly used as susceptible targets to assess NK cell cytotoxicity did not express nectin-1 on their surface and were resistant to HSV infection. When expressed in K562 cells, nectin-1-GFP accumulated at cell contacts and allowed HSV entry. Furthermore, overexpression of nectin-1-GFP led to an increased susceptibility of K562 cells to NK-92 cell cytotoxicity.

DNAM-1 and the TIGIT/PVRIG/TACTILE Axis: Novel Immune Checkpoints for Natural Killer Cell-Based Cancer Immunotherapy

“…In addition to CD112 and CD155, other Nectins have been recently identified as ligands for TACTILE and TIGIT. Thus, CD111 (Nectin-1 or PVRL1) that was previously described as a receptor for herpes viruses [48] is also a ligand for TACTILE [49], and CD113 (Nectin-3 or PVRL3), that originally was described as a member of Ig-like cell adhesion molecules [50], has recently been identified as a ligand for TIGIT [51].…”

“…TACTILE is constitutively expressed on resting human and murine NK cells and mediates NK cell-target cell adhesion by interacting with CD155 [40]. In addition, it has been shown that TACTILE also binds to CD111 [23,49,85] (Figure 1).…”

TIGIT Blockade: A Multipronged Approach to Target the HIV Reservoir

“…DNAM-1 interacts with both PVR and PVRL2 to counter inhibition, yet does so with lower affinity than either TIGIT or PVRIG. TACTILE preferentially interacts with PVRL1 over PVR (Holmes et al, 2019). The affinity of KIR2DL5 for PVR binding is currently unknown, as is whether any other nectin or nectin-like ligand or receptor can serve as its binding partner.…”

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

“…As opposed to DNAM-1, CD96 and TIGIT are inhibitory receptors that, by competing with DNAM-1 for binding to the same ligands, counteract NK cell activation [50]. In particular, CD96 binds PVR [51,52] while TIGIT binds both Nectin-2 and PVR [53,54] (Figure 1). Of note, several nectins are used as entry receptors by different human and animal viruses, thus the expression of both CD96 and TIGIT and their ability to compete with DNAM-1 for the engagement of such ligands are crucial in determining the fate of NK cells in mediating the anti-viral response [55].…”