Exploring the dynamic of NKG2D/NKG2DL axis: A central regulator of NK cell functions

Caterina Marangio; Rosa Molfetta; Erisa Putro; Alessia Carnevale; Rossella Paolini; Caterina Marangio; Rosa Molfetta; Erisa Putro; Alessia Carnevale; Rossella Paolini

doi:10.3934/Allergy.2025005

AIMS Allergy and Immunology

2025, Volume 9, Issue 2: 70-88. doi: 10.3934/Allergy.2025005

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Review

Exploring the dynamic of NKG2D/NKG2DL axis: A central regulator of NK cell functions

Department of Molecular Medicine, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy

Received: 03 March 2025 Revised: 30 April 2025 Accepted: 09 May 2025 Published: 13 May 2025

Natural killer (NK) cells are cytotoxic innate lymphocytes that represent the first line of defense against pathogen infections and tumor growth thanks to their ability to kill cancerous or infected cells and release pro-inflammatory cytokines. NK cell activation is regulated by the expression of a wide array of inhibitory receptors for MHC-I molecules and activating receptors, including NKG2D, which recognize self-ligands upregulated on stressed and damaged cells. Even though the expression of NKG2D ligands (NKG2DL) flags the target cells for NK cell-mediated elimination, a persistent interaction of NKG2D with its ligands promotes receptor downregulation, mainly through the internalization and lysosomal degradation of NKG2D/NKG2DL complexes, thus leading to an exhausted phenotype. On both human and murine NK cells, this phenotype is characterized by the down-modulation of the cytolytic machinery and the upregulation of inhibitory receptors.
In this review, we discuss the current knowledge on the contribution of the NKG2D/NKG2DL axis in both NK cell-mediated clearance of infected and transformed cells and in the dysregulation of NK cell activity due to chronic exposure to NKG2DLs during tumorigenesis.
- Innate immunity,
- NK cells,
- NKG2D,
- NKG2D ligands,
- immune surveillance
Citation: Caterina Marangio, Rosa Molfetta, Erisa Putro, Alessia Carnevale, Rossella Paolini. Exploring the dynamic of NKG2D/NKG2DL axis: A central regulator of NK cell functions[J]. AIMS Allergy and Immunology, 2025, 9(2): 70-88. doi: 10.3934/Allergy.2025005

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Abstract

Natural killer (NK) cells are cytotoxic innate lymphocytes that represent the first line of defense against pathogen infections and tumor growth thanks to their ability to kill cancerous or infected cells and release pro-inflammatory cytokines. NK cell activation is regulated by the expression of a wide array of inhibitory receptors for MHC-I molecules and activating receptors, including NKG2D, which recognize self-ligands upregulated on stressed and damaged cells. Even though the expression of NKG2D ligands (NKG2DL) flags the target cells for NK cell-mediated elimination, a persistent interaction of NKG2D with its ligands promotes receptor downregulation, mainly through the internalization and lysosomal degradation of NKG2D/NKG2DL complexes, thus leading to an exhausted phenotype. On both human and murine NK cells, this phenotype is characterized by the down-modulation of the cytolytic machinery and the upregulation of inhibitory receptors.

In this review, we discuss the current knowledge on the contribution of the NKG2D/NKG2DL axis in both NK cell-mediated clearance of infected and transformed cells and in the dysregulation of NK cell activity due to chronic exposure to NKG2DLs during tumorigenesis.

Acknowledgments

We apologize to all our colleagues whose important work could not be cited directly. Most of these references can be found in the review articles cited in the manuscript.

Conflict of interest

All authors declare that they have no conflict of interest in this paper.

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