Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6
Abstract Natural killer (NK) cell development and functionality rely on precise regulation by specific transcription factors (TFs). Our study demonstrates that the nuclear orphan receptor NR2F6 represses the expression of the activating receptor NKp46, an established key player in NK cell-mediated c...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07407-4 |
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| author | Johannes Woelk Florian Hornsteiner Stephanie Aschauer-Wallner Patrizia Stoitzner Gottfried Baier Natascha Hermann-Kleiter |
| author_facet | Johannes Woelk Florian Hornsteiner Stephanie Aschauer-Wallner Patrizia Stoitzner Gottfried Baier Natascha Hermann-Kleiter |
| author_sort | Johannes Woelk |
| collection | DOAJ |
| description | Abstract Natural killer (NK) cell development and functionality rely on precise regulation by specific transcription factors (TFs). Our study demonstrates that the nuclear orphan receptor NR2F6 represses the expression of the activating receptor NKp46, an established key player in NK cell-mediated cytotoxicity during infection and tumor rejection. Despite normal NK cell development in the bone marrow, germline Nr2f6-deficient mice exhibit impaired terminal maturation of NK cells in the periphery. Short-term NK cell responses to lipopolysaccharide (LPS) activation, independent of NKp46, are subsequently reduced in Nr2f6-deficient mice. Conventional type 1 dendritic cells (cDC1) and macrophage populations are decreased in spleens of Nr2f6-deficient mice, subsequently, IL-15-dependent NK cell priming is limited. Administration of exogenous IL-15 in vitro and as IL-15 complex in vivo can compensate for these deficits, promoting terminal maturation of NK cells in Nr2f6-deficient mice. Subsequent transcriptome analysis reveals significant changes in gene expression profiles of NK cells from IL-15 complex treated Nr2f6-deficient mice, with notable alterations in essential NK genes such as Klrg1, Prdm1, Stat5a, Zeb2, and Prf1. Consequently, Nr2f6-deficient IL-15 complex-treated NK cells raise enhanced effector responses of IFNγ, Perforin, and Granzyme B upon ex vivo activation. Of importance, Nr2f6-deficient mice are protected against MHC-I negative B16-F10 melanoma lung metastasis formation, especially with IL-15 complex treatment, indicating the potential of NR2F6 to affect NKp46-dependent NK cell-mediated tumor surveillance. The therapeutic targeting of NR2F6 may be a promising strategy for boosting NKp46-dependent NK-cell-mediated tumor surveillance and metastasis. |
| format | Article |
| id | doaj-art-758aadb87c654ff590dc9789fd447e1f |
| institution | Kabale University |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-758aadb87c654ff590dc9789fd447e1f2025-02-09T12:56:48ZengNature Publishing GroupCell Death and Disease2041-48892025-02-0116111410.1038/s41419-025-07407-4Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6Johannes Woelk0Florian Hornsteiner1Stephanie Aschauer-Wallner2Patrizia Stoitzner3Gottfried Baier4Natascha Hermann-Kleiter5Institute of Cell Genetics, Department for Genetics and Pharmacology, Medical University of InnsbruckDepartment of Dermatology, Venereology & Allergology, Medical University of InnsbruckLaboratory of Tumor Immunology, Tyrolean Cancer Institute & Internal Medicine V, Medical University of InnsbruckDepartment of Dermatology, Venereology & Allergology, Medical University of InnsbruckInstitute of Cell Genetics, Department for Genetics and Pharmacology, Medical University of InnsbruckInstitute of Cell Genetics, Department for Genetics and Pharmacology, Medical University of InnsbruckAbstract Natural killer (NK) cell development and functionality rely on precise regulation by specific transcription factors (TFs). Our study demonstrates that the nuclear orphan receptor NR2F6 represses the expression of the activating receptor NKp46, an established key player in NK cell-mediated cytotoxicity during infection and tumor rejection. Despite normal NK cell development in the bone marrow, germline Nr2f6-deficient mice exhibit impaired terminal maturation of NK cells in the periphery. Short-term NK cell responses to lipopolysaccharide (LPS) activation, independent of NKp46, are subsequently reduced in Nr2f6-deficient mice. Conventional type 1 dendritic cells (cDC1) and macrophage populations are decreased in spleens of Nr2f6-deficient mice, subsequently, IL-15-dependent NK cell priming is limited. Administration of exogenous IL-15 in vitro and as IL-15 complex in vivo can compensate for these deficits, promoting terminal maturation of NK cells in Nr2f6-deficient mice. Subsequent transcriptome analysis reveals significant changes in gene expression profiles of NK cells from IL-15 complex treated Nr2f6-deficient mice, with notable alterations in essential NK genes such as Klrg1, Prdm1, Stat5a, Zeb2, and Prf1. Consequently, Nr2f6-deficient IL-15 complex-treated NK cells raise enhanced effector responses of IFNγ, Perforin, and Granzyme B upon ex vivo activation. Of importance, Nr2f6-deficient mice are protected against MHC-I negative B16-F10 melanoma lung metastasis formation, especially with IL-15 complex treatment, indicating the potential of NR2F6 to affect NKp46-dependent NK cell-mediated tumor surveillance. The therapeutic targeting of NR2F6 may be a promising strategy for boosting NKp46-dependent NK-cell-mediated tumor surveillance and metastasis.https://doi.org/10.1038/s41419-025-07407-4 |
| spellingShingle | Johannes Woelk Florian Hornsteiner Stephanie Aschauer-Wallner Patrizia Stoitzner Gottfried Baier Natascha Hermann-Kleiter Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6 Cell Death and Disease |
| title | Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6 |
| title_full | Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6 |
| title_fullStr | Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6 |
| title_full_unstemmed | Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6 |
| title_short | Regulation of NK cell development, maturation, and antitumor responses by the nuclear receptor NR2F6 |
| title_sort | regulation of nk cell development maturation and antitumor responses by the nuclear receptor nr2f6 |
| url | https://doi.org/10.1038/s41419-025-07407-4 |
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