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Open AccessArticle

Secreted Ligands of the NK Cell Receptor NKp30: B7-H6 Is in Contrast to BAG6 Only Marginally Released via Extracellular Vesicles

Institute for Tumor Immunology, Clinic for Hematology, Immunology and Oncology, Philipps University of Marburg, Hans-Meerwein-Strasse 3, 35043 Marburg, Germany
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Academic Editor: Angela Chambery
Int. J. Mol. Sci. 2021, 22(4), 2189; https://doi.org/10.3390/ijms22042189
Received: 25 January 2021 / Revised: 12 February 2021 / Accepted: 15 February 2021 / Published: 22 February 2021
(This article belongs to the Special Issue Cellular Secretomes)
NKp30 (Natural Cytotoxicity Receptor 1, NCR1) is a powerful cytotoxicity receptor expressed on natural killer (NK) cells which is involved in tumor cell killing and the regulation of antitumor immune responses. Ligands for NKp30, including BAG6 and B7-H6, are upregulated in virus-infected and tumor cells but rarely detectable on healthy cells. These ligands are released by tumor cells as part of the cellular secretome and interfere with NK cell activity. BAG6 is secreted via the exosomal pathway, and BAG6-positive extracellular vesicles (EV-BAG6) trigger NK cell cytotoxicity and cytokine release, whereas the soluble protein diminishes NK cell activity. However, the extracellular format and activity of B7-H6 remain elusive. Here, we used HEK293 as a model cell line to produce recombinant ligands and to study their impact on NK cell activity. Using this system, we demonstrate that soluble B7-H6 (sB7-H6), like soluble BAG6 (sBAG6), inhibits NK cell-mediated target cell killing. This was associated with a diminished cell surface expression of NKG2D and NCRs (NKp30, NKp40, and NKp46). Strikingly, a reduced NKp30 mRNA expression was observed exclusively in response to sBAG6. Of note, B7-H6 was marginally released in association with EVs, and EVs collected from B7-H6 expressing cells did not stimulate NK cell-mediated killing. The molecular analysis of EVs on a single EV level using nano flow cytometry (NanoFCM) revealed a similar distribution of vesicle-associated tetraspanins within EVs purified from wildtype, BAG6, or B7-H6 overexpressing cells. NKp30 is a promising therapeutic target to overcome NK cell immune evasion in cancer patients, and it is important to unravel how extracellular NKp30 ligands inhibit NK cell functions. View Full-Text
Keywords: extracellular ligands; BAG6; B7-H6; NKp30; tumor cell killing extracellular ligands; BAG6; B7-H6; NKp30; tumor cell killing
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MDPI and ACS Style

Ponath, V.; Hoffmann, N.; Bergmann, L.; Mäder, C.; Alashkar Alhamwe, B.; Preußer, C.; Pogge von Strandmann, E. Secreted Ligands of the NK Cell Receptor NKp30: B7-H6 Is in Contrast to BAG6 Only Marginally Released via Extracellular Vesicles. Int. J. Mol. Sci. 2021, 22, 2189. https://doi.org/10.3390/ijms22042189

AMA Style

Ponath V, Hoffmann N, Bergmann L, Mäder C, Alashkar Alhamwe B, Preußer C, Pogge von Strandmann E. Secreted Ligands of the NK Cell Receptor NKp30: B7-H6 Is in Contrast to BAG6 Only Marginally Released via Extracellular Vesicles. International Journal of Molecular Sciences. 2021; 22(4):2189. https://doi.org/10.3390/ijms22042189

Chicago/Turabian Style

Ponath, Viviane; Hoffmann, Nathalie; Bergmann, Leonie; Mäder, Christina; Alashkar Alhamwe, Bilal; Preußer, Christian; Pogge von Strandmann, Elke. 2021. "Secreted Ligands of the NK Cell Receptor NKp30: B7-H6 Is in Contrast to BAG6 Only Marginally Released via Extracellular Vesicles" Int. J. Mol. Sci. 22, no. 4: 2189. https://doi.org/10.3390/ijms22042189

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