FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development

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.

Interactions of IDO and the Kynurenine Pathway with Cell Transduction Systems and Metabolism at the Inflammation–Cancer Interface

“…Any modulation of this route by interference with FOXO1 may therefore modulate chemosensitivity of CRC and present a novel target for treatment. A similar argument applies to the differentiation of NK cells, as FOXO1 and FOXO3 are necessary for normal development of the NK lineage and innate lymphoid cells [167] by modifying the expression of IL-15Rβ. Disrupting FOXO1/3 may have widespread implications for immune system function.…”

FOXO1 orchestrates the intestinal homeostasis via neuronal signaling in group 3 innate lymphoid cells

“…However, we did not observe a significant change in the cell number of ILC3s in Foxo1 -deficient mice, indicating a different regulatory mechanism mediated by FOXO1 in ILC3s. Luu et al found that ILC3 numbers were decreased in BM and thymus, and in contrast, NKp46 − ILC3s were increased in spleen of Foxo1,3 ΔVav mice compared with WT mice ( Luu et al, 2022 ). By using Vav-Cre, Foxo1 gene was depleted in all hematopoietic cells, including the progenitor cells.…”

FoxO Transcription Factors: Applicability as a Novel Immune Cell Regulators and Therapeutic Targets in Oxidative Stress-Related Diseases

“…Deng et al reported that FoxO1 is dispensable for NK cell development and that inactivation of FoxO1 is required for T-bet expression [ 94 ]. Furthermore, Luu et al reported that the combined loss of FoxO1 and FoxO3 caused specific changes in the composition of noncytotoxic innate lymphoid cell subsets in the BM, thymus, and spleen [ 95 ]. They also revealed that FoxO transcription factors ensure proper NK cell development at various lineage commitment stages by orchestrating distinct molecular mechanisms.…”