Transcription Factor Foxo1 is a Negative Regulator of Natural Killer Cell Maturation and Function

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2015 Mar 15

PMID 25769609

Citations 103

Authors

Youcai Deng

Yann Kerdiles

Jianhong Chu

Shunzong Yuan

Youwei Wang

Xilin Chen

Hsiaoyin Mao

Lingling Zhang

Jianying Zhang

Tiffany Hughes

Yafei Deng

Qi Zhang

Fangjie Wang

Xianghong Zou

Chang-Gong Liu

Aharon G Freud

Xiaohui Li

Michael A Caligiuri

Eric Vivier

Jianhua Yu

Affiliations

Soon will be listed here.

Abstract

Little is known about the role of negative regulators in controlling natural killer (NK) cell development and effector functions. Foxo1 is a multifunctional transcription factor of the forkhead family. Using a mouse model of conditional deletion in NK cells, we found that Foxo1 negatively controlled NK cell differentiation and function. Immature NK cells expressed abundant Foxo1 and little Tbx21 relative to mature NK cells, but these two transcription factors reversed their expression as NK cells proceeded through development. Foxo1 promoted NK cell homing to lymph nodes by upregulating CD62L expression and inhibited late-stage maturation and effector functions by repressing Tbx21 expression. Loss of Foxo1 rescued the defect in late-stage NK cell maturation in heterozygous Tbx21(+/-) mice. Collectively, our data reveal a regulatory pathway by which the negative regulator Foxo1 and the positive regulator Tbx21 play opposing roles in controlling NK cell development and effector functions.

Citing Articles

High-fat intake during lactation ameliorates cardiac fatty acid metabolic disorders and dysfunction in mouse offspring undergoing prenatal poly (I:C) stimulation.

Song L, Meng M, Ji Y, Peng J, Guan X, Yang Y Acta Pharmacol Sin. 2025; .

PMID: 40000881 DOI: 10.1038/s41401-025-01497-8.

inhibits the cytotoxicity of primary natural killer cells.

Abdelbary R, Ragheb M, El Sobky S, El-Badri N, Aboud N, Tawheed A Front Oncol. 2025; 14:1523068.

PMID: 39906666 PMC: 11790671. DOI: 10.3389/fonc.2024.1523068.

Turning Cancer Immunotherapy to the Emerging Immune Checkpoint TIGIT: Will This Break Through the Limitations of the Legacy Approach?.

Cui H, Elkord E Vaccines (Basel). 2025; 12(12.

PMID: 39771968 PMC: 11679306. DOI: 10.3390/vaccines12121306.

Immune regulation: a new strategy for traditional Chinese medicine-based treatment of granulomatous lobular mastitis.

Lou Y, Xu H, Lu Z, Wang B, Liu X Front Immunol. 2024; 15:1494155.

PMID: 39544943 PMC: 11560460. DOI: 10.3389/fimmu.2024.1494155.

Comprehensive snapshots of natural killer cells functions, signaling, molecular mechanisms and clinical utilization.

Chen S, Zhu H, Jounaidi Y Signal Transduct Target Ther. 2024; 9(1):302.

PMID: 39511139 PMC: 11544004. DOI: 10.1038/s41392-024-02005-w.

References

Deng Y, Chu J, Ren Y, Fan Z, Ji X, Mundy-Bosse B . The natural product phyllanthusmin C enhances IFN-γ production by human NK cells through upregulation of TLR-mediated NF-κB signaling. J Immunol. 2014; 193(6):2994-3002. PMC: 4162489. DOI: 10.4049/jimmunol.1302600. View

Vivier E, Ugolini S, Blaise D, Chabannon C, Brossay L . Targeting natural killer cells and natural killer T cells in cancer. Nat Rev Immunol. 2012; 12(4):239-52. PMC: 5161343. DOI: 10.1038/nri3174. View

Ouyang W, Liao W, Luo C, Yin N, Huse M, Kim M . Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature. 2012; 491(7425):554-9. PMC: 3771531. DOI: 10.1038/nature11581. View

Calnan D, Brunet A . The FoxO code. Oncogene. 2008; 27(16):2276-88. DOI: 10.1038/onc.2008.21. View

Huntington N, Tabarias H, Fairfax K, Brady J, Hayakawa Y, Degli-Esposti M . NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J Immunol. 2007; 178(8):4764-70. DOI: 10.4049/jimmunol.178.8.4764. View

Tong Q, He S, Xie F, Mochizuki K, Liu Y, Mochizuki I . Ezh2 regulates transcriptional and posttranslational expression of T-bet and promotes Th1 cell responses mediating aplastic anemia in mice. J Immunol. 2014; 192(11):5012-22. PMC: 4075972. DOI: 10.4049/jimmunol.1302943. View

Luevano M, Madrigal A, Saudemont A . Transcription factors involved in the regulation of natural killer cell development and function: an update. Front Immunol. 2012; 3:319. PMC: 3470934. DOI: 10.3389/fimmu.2012.00319. View

Yun S, Lee S, Yoon S, Kim M, Piao Z, Myung P . TOX regulates the differentiation of human natural killer cells from hematopoietic stem cells in vitro. Immunol Lett. 2010; 136(1):29-36. DOI: 10.1016/j.imlet.2010.11.008. View

Marcoe J, Lim J, Schaubert K, Fodil-Cornu N, Matka M, McCubbrey A . TGF-β is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy. Nat Immunol. 2012; 13(9):843-50. PMC: 3426626. DOI: 10.1038/ni.2388. View

10.

Staron M, Gray S, Marshall H, Parish I, Chen J, Perry C . The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity. 2014; 41(5):802-14. PMC: 4270830. DOI: 10.1016/j.immuni.2014.10.013. View

11.

Townsend M, Weinmann A, Matsuda J, Salomon R, Farnham P, Biron C . T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity. 2004; 20(4):477-94. DOI: 10.1016/s1074-7613(04)00076-7. View

12.

Zwaagstra J, Sulea T, Baardsnes J, Lenferink A, Collins C, Cantin C . Engineering and therapeutic application of single-chain bivalent TGF-β family traps. Mol Cancer Ther. 2012; 11(7):1477-87. DOI: 10.1158/1535-7163.MCT-12-0060. View

13.

Yu J, Mao H, Wei M, Hughes T, Zhang J, Park I . CD94 surface density identifies a functional intermediary between the CD56bright and CD56dim human NK-cell subsets. Blood. 2009; 115(2):274-81. PMC: 2808153. DOI: 10.1182/blood-2009-04-215491. View

14.

Di Santo J . Natural killer cell developmental pathways: a question of balance. Annu Rev Immunol. 2006; 24:257-86. DOI: 10.1146/annurev.immunol.24.021605.090700. View

15.

Allan D, Rybalov B, Awong G, Zuniga-Pflucker J, Kopcow H, Carlyle J . TGF-β affects development and differentiation of human natural killer cell subsets. Eur J Immunol. 2010; 40(8):2289-95. PMC: 3066635. DOI: 10.1002/eji.200939910. View

16.

Yu J, Freud A, Caligiuri M . Location and cellular stages of natural killer cell development. Trends Immunol. 2013; 34(12):573-82. PMC: 3852183. DOI: 10.1016/j.it.2013.07.005. View

17.

Ramirez K, Kee B . Multiple hats for natural killers. Curr Opin Immunol. 2010; 22(2):193-8. PMC: 3388277. DOI: 10.1016/j.coi.2010.02.002. View

18.

Hayakawa Y, Smyth M . CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J Immunol. 2006; 176(3):1517-24. DOI: 10.4049/jimmunol.176.3.1517. View

19.

Gordon S, Chaix J, Rupp L, Wu J, Madera S, Sun J . The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity. 2012; 36(1):55-67. PMC: 3381976. DOI: 10.1016/j.immuni.2011.11.016. View

20.

Li H, Liang J, Castrillon D, DePinho R, Olson E, Liu Z . FoxO4 regulates tumor necrosis factor alpha-directed smooth muscle cell migration by activating matrix metalloproteinase 9 gene transcription. Mol Cell Biol. 2007; 27(7):2676-86. PMC: 1899894. DOI: 10.1128/MCB.01748-06. View