FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development.

Autor:	Luu TT; Department of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, Sweden.; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden., Søndergaard JN; Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden., Peña-Pérez L; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden., Kharazi S; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden., Krstic A; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden., Meinke S; Department of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, Sweden.; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden., Schmied L; Department of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, Sweden.; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden., Frengen N; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden., Heshmati Y; Department of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, Sweden.; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden., Kierczak M; Department of Cell and Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden., Bouderlique T; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden., Wagner AK; Department of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, Sweden.; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden., Gustafsson C; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden., Chambers BJ; Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden., Achour A; Science for Life Laboratory, Department of Medicine Solna, Karolinska Institute, and Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden., Kutter C; Department of Microbiology, Tumor and Cell Biology, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden., Höglund P; Department of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, Sweden.; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.; Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden., Månsson R; Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden.; Department of Hematology, Karolinska University Hospital, Stockholm, Sweden., Kadri N; Science for Life Laboratory, Department of Medicine Solna, Karolinska Institute, and Division of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Jun 09; Vol. 13, pp. 854312. Date of Electronic Publication: 2022 Jun 09 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.854312
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Luu, Søndergaard, Peña-Pérez, Kharazi, Krstic, Meinke, Schmied, Frengen, Heshmati, Kierczak, Bouderlique, Wagner, Gustafsson, Chambers, Achour, Kutter, Höglund, Månsson and Kadri.)
Databáze:	MEDLINE
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