NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity
Abstract NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-α (IL-2Rα) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NK...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55923-w |
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| author | Rui Ma Zhenlong Li Hejun Tang Xiaojin Wu Lei Tian Zahir Shah Ningyuan Liu Tasha Barr Jianying Zhang Sean Wang Srividya Swaminathan Guido Marcucci Yong Peng Michael A. Caligiuri Jianhua Yu |
| author_facet | Rui Ma Zhenlong Li Hejun Tang Xiaojin Wu Lei Tian Zahir Shah Ningyuan Liu Tasha Barr Jianying Zhang Sean Wang Srividya Swaminathan Guido Marcucci Yong Peng Michael A. Caligiuri Jianhua Yu |
| author_sort | Rui Ma |
| collection | DOAJ |
| description | Abstract NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-α (IL-2Rα) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NKp46 reduces IL-2Rα on ILC1s by downregulating NF-κB signaling, thus impairing ILC1 proliferation and cytotoxicity in vitro and in vivo. The binding of anti-NKp46 antibody to NKp46 triggers the activation of NF-κB, the expression of IL-2Rα, interferon-γ (IFN-γ), tumor necrosis factor (TNF), proliferation, and cytotoxicity. Functionally, NKp46 expressed on mouse ILC1s interacts with tumor cells through cell–cell contact, increasing ILC1 production of IFN-γ and TNF, and enhancing cytotoxicity. In a mouse model of acute myeloid leukemia, deletion of NKp46 impairs the ability of ILC1s to control tumor growth and reduces survival. This can be reversed by injecting NKp46+ ILC1s into NKp46 knock-out mice. Human NKp46+ ILC1s exhibit stronger cytokine production and cytotoxicity than their NKp46− counterparts, suggesting that NKp46 plays a similar role in humans. These findings identify an NKp46–NF-κB–IL-2Rα axis and suggest that activating NKp46 with an anti-NKp46 antibody may provide a potential strategy for anti-tumor innate immunity. |
| format | Article |
| id | doaj-art-b9bc529afc23491c972b1fad02e4d3e7 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b9bc529afc23491c972b1fad02e4d3e72025-01-26T12:40:57ZengNature PortfolioNature Communications2041-17232025-01-0116111610.1038/s41467-025-55923-wNKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activityRui Ma0Zhenlong Li1Hejun Tang2Xiaojin Wu3Lei Tian4Zahir Shah5Ningyuan Liu6Tasha Barr7Jianying Zhang8Sean Wang9Srividya Swaminathan10Guido Marcucci11Yong Peng12Michael A. Caligiuri13Jianhua Yu14Center for Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical CenterDepartment of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical CenterThe First Affiliated Hospital of Soochow UniversityDivision of Hematology & Oncology, Department of Medicine, School of Medicine, University of CaliforniaDepartment of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical CenterDepartment of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical CenterDepartment of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical CenterDepartment of Computational and Quantitative Medicine, City of Hope National Medical CenterDivision of Transfusion Medicine, City of Hope National Medical CenterDepartment of Systems Biology, City of Hope Beckman Research InstituteGehr Family Center for Leukemia Research, Hematologic Malignancies Research Institute, Department of Hematological Malignancies Translational Science, City of Hope National Medical CenterCenter for Molecular Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan UniversityDepartment of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical CenterDivision of Hematology & Oncology, Department of Medicine, School of Medicine, University of CaliforniaAbstract NKp46 is a critical regulator of natural killer (NK) cell immunity, but its function in non-NK innate immune cells remains unclear. Here, we show that NKp46 is indispensable for expressing IL-2 receptor-α (IL-2Rα) by non-NK liver-resident type-1 innate lymphoid cells (ILC1s). Deletion of NKp46 reduces IL-2Rα on ILC1s by downregulating NF-κB signaling, thus impairing ILC1 proliferation and cytotoxicity in vitro and in vivo. The binding of anti-NKp46 antibody to NKp46 triggers the activation of NF-κB, the expression of IL-2Rα, interferon-γ (IFN-γ), tumor necrosis factor (TNF), proliferation, and cytotoxicity. Functionally, NKp46 expressed on mouse ILC1s interacts with tumor cells through cell–cell contact, increasing ILC1 production of IFN-γ and TNF, and enhancing cytotoxicity. In a mouse model of acute myeloid leukemia, deletion of NKp46 impairs the ability of ILC1s to control tumor growth and reduces survival. This can be reversed by injecting NKp46+ ILC1s into NKp46 knock-out mice. Human NKp46+ ILC1s exhibit stronger cytokine production and cytotoxicity than their NKp46− counterparts, suggesting that NKp46 plays a similar role in humans. These findings identify an NKp46–NF-κB–IL-2Rα axis and suggest that activating NKp46 with an anti-NKp46 antibody may provide a potential strategy for anti-tumor innate immunity.https://doi.org/10.1038/s41467-025-55923-w |
| spellingShingle | Rui Ma Zhenlong Li Hejun Tang Xiaojin Wu Lei Tian Zahir Shah Ningyuan Liu Tasha Barr Jianying Zhang Sean Wang Srividya Swaminathan Guido Marcucci Yong Peng Michael A. Caligiuri Jianhua Yu NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity Nature Communications |
| title | NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity |
| title_full | NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity |
| title_fullStr | NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity |
| title_full_unstemmed | NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity |
| title_short | NKp46 enhances type 1 innate lymphoid cell proliferation and function and anti-acute myeloid leukemia activity |
| title_sort | nkp46 enhances type 1 innate lymphoid cell proliferation and function and anti acute myeloid leukemia activity |
| url | https://doi.org/10.1038/s41467-025-55923-w |
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