The Role of Forkhead Box 1 (FOXO1) in the Immune System: Dendritic Cells, T Cells, B Cells, and Hematopoietic Stem Cells

Overview

Journal Crit Rev Immunol

Publisher Begell House

Specialty Allergy & Immunology

Date 2018 Feb 13

PMID 29431075

Citations 46

Authors

Adriana Alicia Cabrera-Ortega

Daniel Feinberg

Youde Liang

Carlos Rossa Jr

Dana T Graves

Affiliations

Soon will be listed here.

Abstract

Forkhead box-O (FOXO) transcription factors have a fundamental role in the development and differentiation of immune cells. FOXO1 and FOXO3 are FOXO members that are structurally similar and bind to the same conserved consensus DNA sequences to induce transcription. FOXO1 has been studied in detail in the activation of dendritic cells (DCs), where it plays an important role through the regulation of target genes such as ICAM-1, CCR7, and the integrin αvβ3. FOXO1 is activated by bacteria challenge in DCs and promotes DC bacterial phagocytosis, migration, homing to lymph nodes, DC stimulation of CD4+ T cells and resting B cells, and antibody production. Deletion of FOXO1 in DCs enhances susceptibility to bacteria-induced periodontal disease. FOXO1 and FOXO3 maintain naive T cell quiescence and survival. FOXO1 and FOXO3 enhance the formation of regulatory T cells and inhibit the formation of T-helper 1 (Th1) and Th17 cells. FOXO1 promotes differentiation, proliferation, survival, immunoglobulin gene rearrangement, and class switching in B cells, but FOXO3 has little effect. Both FOXO1 and FOXO3 are important in the maintenance of hematopoietic stem cells by protecting them from oxidative stress. This review examines FOXO1/FOXO3 in the adaptive immune response, key target genes, and FOXO inhibition by the phosphoinositide 3-kinase/AKT pathway.

Citing Articles

Targeting senescence and GATA4 in age-related cardiovascular disease: a comprehensive approach.

Imran M, Altamimi A, Afzal M, Babu M, Goyal K, Ballal S Biogerontology. 2025; 26(1):45.

PMID: 39831933 DOI: 10.1007/s10522-025-10189-z.

Epigenetic Drift Is Involved in the Efficacy of HBV Vaccination.

Ferraresi F, Anticoli S, Salvioli S, Pirazzini C, Calzari L, Gentilini D Vaccines (Basel). 2025; 12(12.

PMID: 39771992 PMC: 11680278. DOI: 10.3390/vaccines12121330.

miR-132-3p downregulates in CD4 T cells and is associated with disease manifestations in patients with lupus.

Qin H, Chen S, Liu X, Liang J, Wu H, Zhu X J Int Med Res. 2024; 52(10):3000605241286762.

PMID: 39429035 PMC: 11494630. DOI: 10.1177/03000605241286762.

Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment.

Bonilla M, Radyk M, Perricone M, Elhossiny A, Harold A, Medina-Cabrera P JCI Insight. 2024; 9(18).

PMID: 39315547 PMC: 11457849. DOI: 10.1172/jci.insight.180114.

Plasma EV-miRNAs as Potential Biomarkers of COVID-19 Vaccine Immune Response in Cancer Patients.

Almeida B, Dias T, Cruz P, Sousa-Pimenta M, Teixeira A, Pereira C Vaccines (Basel). 2024; 12(8).

PMID: 39203974 PMC: 11359428. DOI: 10.3390/vaccines12080848.

References

Lin Y, Jhunjhunwala S, Benner C, Heinz S, Welinder E, Mansson R . A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat Immunol. 2010; 11(7):635-43. PMC: 2896911. DOI: 10.1038/ni.1891. 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

Lam E, Francis R, Petkovic M . FOXO transcription factors: key regulators of cell fate. Biochem Soc Trans. 2006; 34(Pt 5):722-6. DOI: 10.1042/BST0340722. View

Chung S, Ranjan R, Lee Y, Park G, Karpurapu M, Deng J . Distinct role of FoxO1 in M-CSF- and GM-CSF-differentiated macrophages contributes LPS-mediated IL-10: implication in hyperglycemia. J Leukoc Biol. 2014; 97(2):327-39. PMC: 4304426. DOI: 10.1189/jlb.3A0514-251R. View

Pajvani U, Accili D . The new biology of diabetes. Diabetologia. 2015; 58(11):2459-68. PMC: 4591190. DOI: 10.1007/s00125-015-3722-5. View

Nakagawa S, Gisselbrecht S, Rogers J, Hartl D, Bulyk M . DNA-binding specificity changes in the evolution of forkhead transcription factors. Proc Natl Acad Sci U S A. 2013; 110(30):12349-54. PMC: 3725104. DOI: 10.1073/pnas.1310430110. View

Stadeli R, Hoffmans R, Basler K . Transcription under the control of nuclear Arm/beta-catenin. Curr Biol. 2006; 16(10):R378-85. DOI: 10.1016/j.cub.2006.04.019. View

Wang Y, Brooks S, Li X, Anzelon A, Rickert R, Carter R . The physiologic role of CD19 cytoplasmic tyrosines. Immunity. 2002; 17(4):501-14. DOI: 10.1016/s1074-7613(02)00426-0. View

10.

Geginat J, Nizzoli G, Paroni M, Maglie S, Larghi P, Pascolo S . Immunity to Pathogens Taught by Specialized Human Dendritic Cell Subsets. Front Immunol. 2015; 6:527. PMC: 4603245. DOI: 10.3389/fimmu.2015.00527. View

11.

Reizis B, Colonna M, Trinchieri G, Barrat F, Gilliet M . Plasmacytoid dendritic cells: one-trick ponies or workhorses of the immune system?. Nat Rev Immunol. 2011; 11(8):558-65. PMC: 4157822. DOI: 10.1038/nri3027. View

12.

Anderson M, Viars C, Czekay S, Cavenee W, Arden K . Cloning and characterization of three human forkhead genes that comprise an FKHR-like gene subfamily. Genomics. 1998; 47(2):187-99. DOI: 10.1006/geno.1997.5122. View

13.

Birkenkamp K, Coffer P . Regulation of cell survival and proliferation by the FOXO (Forkhead box, class O) subfamily of Forkhead transcription factors. Biochem Soc Trans. 2003; 31(Pt 1):292-7. DOI: 10.1042/bst0310292. View

14.

Harada Y, Harada Y, Elly C, Ying G, Paik J, DePinho R . Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med. 2010; 207(7):1381-91. PMC: 2901074. DOI: 10.1084/jem.20100004. View

15.

Obsilova V, Vecer J, Herman P, Pabianova A, Sulc M, Teisinger J . 14-3-3 Protein interacts with nuclear localization sequence of forkhead transcription factor FoxO4. Biochemistry. 2005; 44(34):11608-17. DOI: 10.1021/bi050618r. View

16.

Delgoffe G, Woo S, Turnis M, Gravano D, Guy C, Overacre A . Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature. 2013; 501(7466):252-6. PMC: 3867145. DOI: 10.1038/nature12428. View

17.

Ouyang W, Li M . Foxo: in command of T lymphocyte homeostasis and tolerance. Trends Immunol. 2010; 32(1):26-33. PMC: 3053075. DOI: 10.1016/j.it.2010.10.005. View

18.

Fan W, Morinaga H, Kim J, Bae E, Spann N, Heinz S . FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. 2010; 29(24):4223-36. PMC: 3018786. DOI: 10.1038/emboj.2010.268. View

19.

Tikhanovich I, Cox J, Weinman S . Forkhead box class O transcription factors in liver function and disease. J Gastroenterol Hepatol. 2013; 28 Suppl 1:125-31. PMC: 3937070. DOI: 10.1111/jgh.12021. View

20.

Lin L, Hron J, Peng S . Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity. 2004; 21(2):203-13. DOI: 10.1016/j.immuni.2004.06.016. View