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CD155 density on target cells drives divergent natural killer cell responses owing to DNAM-1 loss
Philippa M Saunders1, Clare V L Oates1, Roseanna Hare2
1Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Australia.
Abstract:
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.
Insights
Natural killer (NK) cell activation via CD155 requires specific ligand density. Low CD155 levels boost NK cell responses, while high levels cause receptor downregulation without enhancing activation.
Area of Science:
- Immunology
- Cellular Biology
- Cancer Research
Background:
- Natural killer (NK) cells are crucial for tumor surveillance, recognizing transformed cells through activating and inhibitory receptors.
- DNAM-1 is a key activating receptor involved in NK cell recognition of tumor cells expressing CD155.
- High CD155 expression in cancers often correlates with poor clinical outcomes, suggesting complex regulatory roles.
Purpose of the Study:
- To investigate how varying densities of the ligand CD155 on target cells influence NK cell activation and function.
- To elucidate the impact of CD155 ligand density on DNAM-1 receptor expression and NK cell effector responses, particularly IFN-γ production.
Main Methods:
- Comparative analysis of NK cell recognition of target cells engineered to express low versus high levels of CD155.
- Assessment of NK cell activation markers, including IFN-γ production and DNAM-1/TIGIT receptor surface expression.
- Gene editing techniques were used to evaluate the role of TIGIT in NK cell recognition.
Main Results:
- Low CD155 expression enhanced NK cell activation, notably increasing IFN-γ responses.
- High CD155 expression induced rapid, activation-dependent downregulation of DNAM-1, without augmenting IFN-γ responses.
- High CD155 also led to TIGIT loss, but TIGIT deficiency did not significantly impair target cell recognition.
- DNAM-1 engagement was confirmed as the mediator of improved activation at low CD155 levels.
- Recognition of CD112-expressing targets also resulted in DNAM-1 loss and heightened IFN-γ responses.
Conclusions:
- NK cell activation via DNAM-1 is finely tuned by ligand density; low avidity engagement enhances NK cell responses, particularly IFN-γ secretion.
- Conversely, high avidity engagement leads to DNAM-1 downregulation, diminishing effector functions rather than enhancing them.
- These findings highlight the critical role of ligand density in modulating NK cell-mediated anti-tumor immunity.
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