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.
Holmes, Veronica M; Maluquer de Motes, Carlos; Richards, Paige T; Roldan, Jessenia; Bhargava, Arjun K; Orange, Jordan S; and Krummenacher, Claude, "Interaction between nectin-1 and the human natural killer cell receptor CD96." (2019). Faculty Scholarship for the College of Science & Mathematics. 126.
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Holmes, V.M., Maluquer de Motes, C., Richards, P.T., Roldan, J., Bhargava, A.K., Orange, J.S., & Krummenacher, C.. (2019) Interaction between nectin-1 and the human natural killer cell receptor CD96. PLoS One. 2019 Feb 13;14(2):e0212443. doi:10.1371/journal.pone.0212443.