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

Area of Science:

• Immunology
• Cell Adhesion Molecules
• Virology

Background:

• Natural Killer (NK) cell activity is regulated by activating and inhibitory signals at the immunological synapse.
• NK cells utilize paired immunoglobulin-like receptors, including CD226 (DNAM-1), TIGIT, and CD96, which bind to nectin family adhesion molecules.
• CD96 function differs between human and mouse models, with human CD96 activating NK cells via CD155, while mouse CD96 is associated with decreased NK cell activation and binds nectin-1.

Purpose of the Study:

• To investigate the interaction between human nectin-1 and the NK cell receptor CD96.
• To characterize the functional consequences of the nectin-1 and CD96 interaction on NK cell activity and target cell susceptibility.

Main Methods:

• In vitro binding assays to assess the interaction between human nectin-1 and CD96.
• Analysis of binding affinity using surface plasmon resonance.
• Expression of nectin-1 in K562 cells and assessment of NK cell cytotoxicity and herpes simplex virus (HSV) entry.

Main Results:

• Human nectin-1 directly interacts with CD96 in vitro, with binding occurring on the nectin-1 V-domain.
• The affinity of nectin-1 for CD96 is lower than for other nectins but comparable to its affinity for HSV glycoprotein D (gD).
• Human CD96 exhibits lower affinity for nectin-1 compared to its known ligand CD155.
• Nectin-1 expression in K562 cells, which lack endogenous nectin-1, leads to accumulation at cell contacts, facilitates HSV entry, and increases susceptibility to NK-92 cell-mediated cytotoxicity.

Conclusions:

• Human nectin-1 directly binds to CD96, suggesting a novel interaction pathway in NK cell regulation.
• The interaction between nectin-1 and CD96 influences NK cell cytotoxicity and susceptibility to viral entry.
• Nectin-1 expression can modulate target cell recognition and killing by NK cells.