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FOXO1 和 FOXO3 协同调控固有淋巴细胞发育。

FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development.

机构信息

Department of Medicine Huddinge, Huddinge, Karolinska Institute, Stockholm, Sweden.

Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institute, Stockholm, Sweden.

出版信息

Front Immunol. 2022 Jun 9;13:854312. doi: 10.3389/fimmu.2022.854312. eCollection 2022.

DOI:10.3389/fimmu.2022.854312
PMID:35757763
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9218573/
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 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.

摘要

自然杀伤 (NK) 细胞在清除病毒和早期监测恶性转化方面发挥作用，但我们对控制其发育和功能的潜在机制的了解仍不完整。为了揭示 NK 细胞前体细胞 (NKP) 中决定细胞命运的途径，我们利用了一种无偏方法，生成了 NK 细胞前体细胞的综合基因表达谱。我们发现 NK 细胞程序在 CLP 到 preNKP 和 preNKP 到 rNKP 的转变过程中逐渐建立。与 FOXO1 和 FOXO3 通过 NK 发育轨迹共同表达一致，两者的缺失扰乱了 NK 细胞程序的建立，并导致 NK 细胞发育和成熟停滞。此外，我们发现 FOXO1 和 FOXO3 的联合缺失导致骨髓、脾脏和胸腺中非细胞毒性固有淋巴细胞 (ILC) 亚群的组成发生特定变化。通过结合转录组和染色质分析，我们揭示了 FOXO TFs 通过协调不同的分子机制，确保 NK 细胞在各个谱系承诺阶段的正常发育。共同的 FOXO1 和 FOXO3 在共同和固有淋巴样细胞祖细胞中的缺失导致与 NK 细胞发育相关的基因表达减少，包括 ETS-1 及其下游靶基因。最后，我们发现 FOXO1 和 FOXO3 控制了 NK 细胞的存活，调节了 rNKP 和骨髓 NK 细胞上 IL-15Rβ (CD122) 的基因表达。总的来说，我们揭示了 FOXO1 和 FOXO3 以协调的方式在多个阶段发挥作用，调节 NK 细胞和 ILC 谱系承诺期间的关键发育基因。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/a4a9d902bf11/fimmu-13-854312-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/ba0485c831c4/fimmu-13-854312-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/df1eb3624d5d/fimmu-13-854312-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/2a292668e401/fimmu-13-854312-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/95cd9227ce9a/fimmu-13-854312-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/41e5ad40b998/fimmu-13-854312-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/a4a9d902bf11/fimmu-13-854312-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/ba0485c831c4/fimmu-13-854312-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/df1eb3624d5d/fimmu-13-854312-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/2a292668e401/fimmu-13-854312-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/95cd9227ce9a/fimmu-13-854312-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/41e5ad40b998/fimmu-13-854312-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/15e0/9218573/a4a9d902bf11/fimmu-13-854312-g006.jpg

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