Frontiers in Immunology (Jun 2022)

FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development

  • 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

DOI
https://doi.org/10.3389/fimmu.2022.854312
Journal volume & issue
Vol. 13

Abstract

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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.

Keywords