NKG2D engagement on human NK cells leads to DNAM-1 hypo-responsiveness through different converging mechanisms
Nadia D Milito1, Alessandra Zingoni1, Helena Stabile1
1Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Abstract:
Natural killer (NK) cell activation is regulated by activating and inhibitory receptors that facilitate diseased cell recognition. Among activating receptors, NKG2D and DNAM-1 play a pivotal role in anticancer immune responses since they bind ligands upregulated on transformed cells. During tumor progression, however, these receptors are frequently downmodulated and rendered functionally inactive. Of note, NKG2D internalization has been associated with the acquisition of a dysfunctional phenotype characterized by the cross-tolerization of unrelated activating receptors. However, our knowledge of the consequences of NKG2D engagement is still incomplete. Here, by cytotoxicity assays combined with confocal microscopy, we demonstrate that NKG2D engagement on human NK cells impairs DNAM-1-mediated killing through two different converging mechanisms: by the upregulation of the checkpoint inhibitory receptor TIGIT, that in turn suppresses DNAM-1-mediated cytotoxic function, and by direct inhibition of DNAM-1-promoted signaling. Our results highlight a novel interplay between NKG2D and DNAM-1/TIGIT receptors that may facilitate neoplastic cell evasion from NK cell-mediated clearance.
Insights
Natural killer (NK) cell receptor NKG2D impairs anticancer immunity by suppressing DNAM-1 function. This occurs via TIGIT upregulation and direct signaling inhibition, aiding tumor evasion.
Area of Science:
- Immunology
- Cancer Biology
- Cellular Signaling
Background:
- Natural killer (NK) cells use activating and inhibitory receptors to identify diseased cells.
- NKG2D and DNAM-1 are key activating receptors in anticancer immunity, but can be downregulated during tumor progression.
- NKG2D internalization is linked to NK cell dysfunction and cross-tolerization of other activating receptors.
Purpose of the Study:
- To investigate the consequences of NKG2D engagement on NK cell function, specifically its impact on DNAM-1-mediated cytotoxicity.
- To elucidate the mechanisms by which NKG2D influences DNAM-1 signaling and NK cell effector functions.
Main Methods:
- Cytotoxicity assays were performed on human NK cells.
- Confocal microscopy was utilized to visualize receptor interactions and cellular events.
- Analysis of NKG2D, DNAM-1, and TIGIT receptor expression and function.
Main Results:
- NKG2D engagement impairs DNAM-1-mediated killing by human NK cells.
- This impairment occurs through two mechanisms: upregulation of the inhibitory receptor TIGIT and direct inhibition of DNAM-1 signaling.
- TIGIT upregulation further suppresses DNAM-1-mediated cytotoxic function.
Conclusions:
- A novel interplay exists between NKG2D, DNAM-1, and TIGIT receptors in NK cells.
- This interaction can facilitate tumor cell evasion from NK cell-mediated immune surveillance.
- Targeting this pathway could enhance NK cell-based cancer immunotherapy.
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