AUTHOR=Luu Thuy T. , Søndergaard Jonas Nørskov , Peña-Pérez Lucía , Kharazi Shabnam , Krstic Aleksandra , Meinke Stephan , Schmied Laurent , Frengen Nicolai , Heshmati Yaser , Kierczak Marcin , Bouderlique Thibault , Wagner Arnika Kathleen , Gustafsson Charlotte , Chambers Benedict J. , Achour Adnane , Kutter Claudia , Höglund Petter , Månsson Robert , Kadri Nadir TITLE=FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.854312 DOI=10.3389/fimmu.2022.854312 ISSN=1664-3224 ABSTRACT=

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.