Journal of immunology (Baltimore, Md. : 1950)Nov 4, 2025

How CD155 Levels Affect Natural Killer Cell Responses

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 1, 2026

Abstract

Low levels of CD155 on target cells can enhance NK cell activation, reflected by increased IFN-γ responses.

NK cell activation is influenced by the density of CD155 on target cells.
Recognition of target cells with low CD155 levels led to elevated IFN-γ production.
High levels of CD155 caused a rapid decrease in the DNAM-1 receptor on NK cells.
Despite the loss of DNAM-1, high CD155 levels did not enhance IFN-γ responses.
TIGIT loss from NK cells was associated with high CD155 levels, but gene editing TIGIT did not significantly affect target recognition.
Low avidity engagement of DNAM-1 improves NK cell activation, while stronger engagement may inhibit effector responses.

Simplified

Activation of natural killer (NK) cells by transformed targets requires the engagement of activating receptors and commonly a concomitant loss of inhibitory signaling. While the coactivating receptor DNAM-1 is involved in NK cell recognition of tumors expressing the nectin-like molecule CD155, in many cancer types, high expression of CD155 is associated with a poor clinical prognosis. To assess the impact of ligand density on NK cell function, recognition of target cells expressing low and high levels of CD155 was compared. While low levels of CD155 on target cells augmented NK cell activation, most evident in elevated IFN-γ responses, high levels of CD155 drove rapid, activation-induced downregulation of DNAM-1 that did not result in enhanced IFN-γ responses. High levels of CD155 also drove TIGIT loss from the NK cell surface; however, gene editing of TIGIT from primary NK cells had no significant impact on target cell recognition. Although low levels of CD155 induced a degree of DNAM-1 loss, the improved activation was still mediated through DNAM-1, as assessed through selective disruption of the interaction. Similarly, NK cell recognition of targets expressing the nectin CD112, which also engages both DNAM-1 and TIGIT, resulted in modest loss of DNAM-1 expression and heightened IFN-γ responses. Together, these observations suggest that DNAM-1 recognition of its ligands is delicately poised such that low avidity receptor engagement augments NK cell activation, and in particular IFN-γ responses, while stronger engagement can result in the rapid downregulation of DNAM-1 without any significant enhancement of effector responses.

Funding

Competing interests

Conflicts of interest . None declared.

PubMed

How CD155 Levels Affect Natural Killer Cell Responses

Abstract

Funding

Competing interests

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