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Article

Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy

1
Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61032 Urbino, Italy
2
INFN-Gran Sasso National Laboratory, Assergi, 67100 L’Aquila, Italy
3
Area Aggregazione Servizi e Laboratori Diagnostici, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy
4
Department of Sensory Organs, Sapienza University of Rome, 00161 Rome, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally.
Cells 2020, 9(3), 753; https://doi.org/10.3390/cells9030753
Received: 11 February 2020 / Revised: 9 March 2020 / Accepted: 13 March 2020 / Published: 19 March 2020
(This article belongs to the Special Issue New Developments of Natural Killer (NK) Cells in Immunotherapy)
The NK cell population is characterized by distinct NK cell subsets that respond differently to the various activating stimuli. For this reason, the determination of the optimal cytotoxic activation of the different NK cell subsets can be a crucial aspect to be exploited to counter cancer cells in oncologic patients. To evaluate how the triggering of different combination of activating receptors can affect the cytotoxic responses of different NK cell subsets, we developed a microbead-based degranulation assay. By using this new assay, we were able to detect CD107a+ degranulating NK cells even within the less cytotoxic subsets (i.e., resting CD56bright and unlicensed CD56dim NK cells), thus demonstrating its high sensitivity. Interestingly, signals delivered by the co-engagement of NKp46 with 2B4, but not with CD2 or DNAM-1, strongly cooperate to enhance degranulation on both licensed and unlicensed CD56dim NK cells. Of note, 2B4 is known to bind CD48 hematopoietic antigen, therefore this observation may provide the rationale why CD56dim subset expansion correlates with successful hematopoietic stem cell transplantation mediated by alloreactive NK cells against host T, DC and leukemic cells, while sparing host non-hematopoietic tissues and graft versus host disease. The assay further confirms that activation of LFA-1 on NK cells leads to their granule polarization, even if, in some cases, this also takes to an inhibition of NK cell degranulation, suggesting that LFA-1 engagement by ICAMs on target cells may differently affect NK cell response. Finally, we observed that NK cells undergo a time-dependent spontaneous (cytokine-independent) activation after blood withdrawal, an aspect that may strongly bias the evaluation of the resting NK cell response. Altogether our data may pave the way to develop new NK cell activation and expansion strategies that target the highly cytotoxic CD56dim NK cells and can be feasible and useful for cancer and viral infection treatment. View Full-Text
Keywords: NK cell biology; NK cell subsets; NK cell activating receptors; cell adhesion molecules; granule polarization; degranulation; cytotoxicity assay; trogocytosis; long-lived memory-like NK cells NK cell biology; NK cell subsets; NK cell activating receptors; cell adhesion molecules; granule polarization; degranulation; cytotoxicity assay; trogocytosis; long-lived memory-like NK cells
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MDPI and ACS Style

Zamai, L.; Del Zotto, G.; Buccella, F.; Gabrielli, S.; Canonico, B.; Artico, M.; Ortolani, C.; Papa, S. Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy. Cells 2020, 9, 753. https://doi.org/10.3390/cells9030753

AMA Style

Zamai L, Del Zotto G, Buccella F, Gabrielli S, Canonico B, Artico M, Ortolani C, Papa S. Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy. Cells. 2020; 9(3):753. https://doi.org/10.3390/cells9030753

Chicago/Turabian Style

Zamai, Loris, Genny Del Zotto, Flavia Buccella, Sara Gabrielli, Barbara Canonico, Marco Artico, Claudio Ortolani, and Stefano Papa. 2020. "Understanding the Synergy of NKp46 and Co-Activating Signals in Various NK Cell Subpopulations: Paving the Way for More Successful NK-Cell-Based Immunotherapy" Cells 9, no. 3: 753. https://doi.org/10.3390/cells9030753

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