Secreted Ligands of the NK Cell Receptor NKp30: B7-H6 Is in Contrast to BAG6 Only Marginally Released via Extracellular Vesicles
| Autor: | Christina Mäder, Christian Preußer, Nathalie Hoffmann, Leonie Bergmann, Viviane Ponath, Bilal Alashkar Alhamwe, Elke Pogge von Strandmann |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
B7 Antigens
Cell Ligands extracellular ligands Article Catalysis lcsh:Chemistry Inorganic Chemistry Extracellular Vesicles medicine Extracellular Humans NKp30 Physical and Theoretical Chemistry Receptor Cytotoxicity lcsh:QH301-705.5 Molecular Biology Spectroscopy Natural Cytotoxicity Triggering Receptor 3 Chemistry Integrin beta1 Organic Chemistry HEK 293 cells BAG6 General Medicine NKG2D Recombinant Proteins Computer Science Applications Cell biology Killer Cells Natural HEK293 Cells medicine.anatomical_structure Cell killing lcsh:Biology (General) lcsh:QD1-999 B7-H6 tumor cell killing Cell culture Tumor Escape K562 Cells Molecular Chaperones |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 2189, p 2189 (2021) Volume 22 Issue 4 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22042189 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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