FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development
Natural killer (NK) cells play roles in viral clearance and early surveillance against malignant transformation, yet our knowledge of the underlying mechanisms controlling their development and functions remain incomplete. To reveal cell fate-determining pathways in NK cell progenitors (NKP), we uti...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.854312/full |
| _version_ | 1818161426693357568 |
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| author | Thuy T. Luu Thuy T. Luu Jonas Nørskov Søndergaard Lucía Peña-Pérez Lucía Peña-Pérez Shabnam Kharazi Shabnam Kharazi Aleksandra Krstic Aleksandra Krstic Stephan Meinke Stephan Meinke Laurent Schmied Laurent Schmied Nicolai Frengen Nicolai Frengen Yaser Heshmati Yaser Heshmati Marcin Kierczak Thibault Bouderlique Thibault Bouderlique Arnika Kathleen Wagner Arnika Kathleen Wagner Charlotte Gustafsson Charlotte Gustafsson Benedict J. Chambers Adnane Achour Claudia Kutter Petter Höglund Petter Höglund Petter Höglund Robert Månsson Robert Månsson Robert Månsson Nadir Kadri |
| author_facet | Thuy T. Luu Thuy T. Luu Jonas Nørskov Søndergaard Lucía Peña-Pérez Lucía Peña-Pérez Shabnam Kharazi Shabnam Kharazi Aleksandra Krstic Aleksandra Krstic Stephan Meinke Stephan Meinke Laurent Schmied Laurent Schmied Nicolai Frengen Nicolai Frengen Yaser Heshmati Yaser Heshmati Marcin Kierczak Thibault Bouderlique Thibault Bouderlique Arnika Kathleen Wagner Arnika Kathleen Wagner Charlotte Gustafsson Charlotte Gustafsson Benedict J. Chambers Adnane Achour Claudia Kutter Petter Höglund Petter Höglund Petter Höglund Robert Månsson Robert Månsson Robert Månsson Nadir Kadri |
| author_sort | Thuy T. Luu |
| collection | DOAJ |
| description | Natural killer (NK) cells play roles in viral clearance and early surveillance against malignant transformation, yet our knowledge of the underlying mechanisms controlling their development and functions remain incomplete. To reveal cell fate-determining pathways in NK cell progenitors (NKP), we utilized an unbiased approach and generated comprehensive gene expression profiles of NK cell progenitors. We found that the NK cell program was gradually established in the CLP to preNKP and preNKP to rNKP transitions. In line with FOXO1 and FOXO3 being co-expressed through the NK developmental trajectory, the loss of both perturbed the establishment of the NK cell program and caused stalling in both NK cell development and maturation. In addition, we found that the combined loss of FOXO1 and FOXO3 caused specific changes to the composition of the non-cytotoxic innate lymphoid cell (ILC) subsets in bone marrow, spleen, and thymus. By combining transcriptome and chromatin profiling, we revealed that FOXO TFs ensure proper NK cell development at various lineage-commitment stages through orchestrating distinct molecular mechanisms. Combined FOXO1 and FOXO3 deficiency in common and innate lymphoid cell progenitors resulted in reduced expression of genes associated with NK cell development including ETS-1 and their downstream target genes. Lastly, we found that FOXO1 and FOXO3 controlled the survival of committed NK cells via gene regulation of IL-15Rβ (CD122) on rNKPs and bone marrow NK cells. Overall, we revealed that FOXO1 and FOXO3 function in a coordinated manner to regulate essential developmental genes at multiple stages during murine NK cell and ILC lineage commitment. |
| first_indexed | 2024-12-11T16:17:35Z |
| format | Article |
| id | doaj.art-c1dc67fc499e4b4183fc91fffcbae0a1 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T16:17:35Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c1dc67fc499e4b4183fc91fffcbae0a12022-12-22T00:58:56ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-06-011310.3389/fimmu.2022.854312854312FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell DevelopmentThuy T. Luu0Thuy T. Luu1Jonas Nørskov Søndergaard2Lucía Peña-Pérez3Lucía Peña-Pérez4Shabnam Kharazi5Shabnam Kharazi6Aleksandra Krstic7Aleksandra Krstic8Stephan Meinke9Stephan Meinke10Laurent Schmied11Laurent Schmied12Nicolai Frengen13Nicolai Frengen14Yaser Heshmati15Yaser Heshmati16Marcin Kierczak17Thibault Bouderlique18Thibault Bouderlique19Arnika Kathleen Wagner20Arnika Kathleen Wagner21Charlotte Gustafsson22Charlotte Gustafsson23Benedict J. Chambers24Adnane Achour25Claudia Kutter26Petter Höglund27Petter Höglund28Petter Höglund29Robert Månsson30Robert Månsson31Robert Månsson32Nadir Kadri33Department of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Laboratory Medicine, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Laboratory Medicine, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Laboratory Medicine, Karolinska Institute, Stockholm, SwedenDepartment of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Laboratory Medicine, Karolinska Institute, Stockholm, SwedenDepartment of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Laboratory Medicine, Karolinska Institute, Stockholm, SwedenDepartment of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Laboratory Medicine, Karolinska Institute, Stockholm, SwedenDepartment of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, SwedenScience for Life Laboratory, Department of Medicine Solna, Karolinska Institute, and Division of Infectious Diseases, Karolinska University Hospital, Stockholm, SwedenDepartment of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, SwedenDepartment of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenClinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, SwedenCenter for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, SwedenDepartment of Laboratory Medicine, Karolinska Institute, Stockholm, SwedenDepartment of Hematology, Karolinska University Hospital, Stockholm, SwedenScience for Life Laboratory, Department of Medicine Solna, Karolinska Institute, and Division of Infectious Diseases, Karolinska University Hospital, Stockholm, SwedenNatural killer (NK) cells play roles in viral clearance and early surveillance against malignant transformation, yet our knowledge of the underlying mechanisms controlling their development and functions remain incomplete. To reveal cell fate-determining pathways in NK cell progenitors (NKP), we utilized an unbiased approach and generated comprehensive gene expression profiles of NK cell progenitors. We found that the NK cell program was gradually established in the CLP to preNKP and preNKP to rNKP transitions. In line with FOXO1 and FOXO3 being co-expressed through the NK developmental trajectory, the loss of both perturbed the establishment of the NK cell program and caused stalling in both NK cell development and maturation. In addition, we found that the combined loss of FOXO1 and FOXO3 caused specific changes to the composition of the non-cytotoxic innate lymphoid cell (ILC) subsets in bone marrow, spleen, and thymus. By combining transcriptome and chromatin profiling, we revealed that FOXO TFs ensure proper NK cell development at various lineage-commitment stages through orchestrating distinct molecular mechanisms. Combined FOXO1 and FOXO3 deficiency in common and innate lymphoid cell progenitors resulted in reduced expression of genes associated with NK cell development including ETS-1 and their downstream target genes. Lastly, we found that FOXO1 and FOXO3 controlled the survival of committed NK cells via gene regulation of IL-15Rβ (CD122) on rNKPs and bone marrow NK cells. Overall, we revealed that FOXO1 and FOXO3 function in a coordinated manner to regulate essential developmental genes at multiple stages during murine NK cell and ILC lineage commitment.https://www.frontiersin.org/articles/10.3389/fimmu.2022.854312/fullinnate lymphocyte cells (ILCs)developmentFOXOnatural killer cellsIL-15 |
| spellingShingle | Thuy T. Luu Thuy T. Luu Jonas Nørskov Søndergaard Lucía Peña-Pérez Lucía Peña-Pérez Shabnam Kharazi Shabnam Kharazi Aleksandra Krstic Aleksandra Krstic Stephan Meinke Stephan Meinke Laurent Schmied Laurent Schmied Nicolai Frengen Nicolai Frengen Yaser Heshmati Yaser Heshmati Marcin Kierczak Thibault Bouderlique Thibault Bouderlique Arnika Kathleen Wagner Arnika Kathleen Wagner Charlotte Gustafsson Charlotte Gustafsson Benedict J. Chambers Adnane Achour Claudia Kutter Petter Höglund Petter Höglund Petter Höglund Robert Månsson Robert Månsson Robert Månsson Nadir Kadri FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development Frontiers in Immunology innate lymphocyte cells (ILCs) development FOXO natural killer cells IL-15 |
| title | FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development |
| title_full | FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development |
| title_fullStr | FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development |
| title_full_unstemmed | FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development |
| title_short | FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development |
| title_sort | foxo1 and foxo3 cooperatively regulate innate lymphoid cell development |
| topic | innate lymphocyte cells (ILCs) development FOXO natural killer cells IL-15 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.854312/full |
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