Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Foxo in the immune system

Abstract

In addition to their key roles in cellular survival, death, proliferation and metabolism, the Foxo subfamily of forkhead (Fox) transcription factors play critical roles in the homeostasis of immune-relevant cells, including T cells, B cells, neutrophils and other non-lymphoid lineages that modulate inflammation in disease states such as inflammatory arthritis and systemic lupus erythematosus. This review summarizes such current and expanding knowledge of the Foxo family members in immunity, and their potential as therapeutic targets in inflammatory disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  • Asada S, Daitoku H, Matsuzaki H, Saito T, Sudo T, Mukai H et al. (2007). Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell Signal 19: 519–527.

    Article  CAS  Google Scholar 

  • Asselin-Labat ML, David M, Biola-Vidamment A, Lecoeuche D, Zennaro MC, Bertoglio J et al. (2004). GILZ, a new target for the transcription factor FoxO3, protects T lymphocytes from interleukin-2 withdrawal-induced apoptosis. Blood 104: 215–223.

    Article  CAS  Google Scholar 

  • Aud D, Peng SL . (2006). Mechanisms of disease: transcription factors in inflammatory arthritis. Nat Clin Prac Rheum 2: 434–442.

    Article  CAS  Google Scholar 

  • Behzad H, Jamil S, Denny TA, Duronio V . (2007). Cytokine-mediated FOXO3a phosphorylation suppresses FasL expression in hemopoietic cell lines: investigations of the role of Fas in apoptosis due to cytokine starvation. Cytokine 38: 74–83.

    Article  CAS  Google Scholar 

  • Birkenkamp KU, Essafi A, van der Vos KE, da Costa M, Hui RC, Holstege F et al. (2007). FOXO3a induces differentiation of Bcr-Abl-transformed cells through transcriptional downregulation of Id1. J Biol Chem 282: 2211–2220.

    Article  CAS  Google Scholar 

  • Bosque A, Aguilo JI, Alava MA, Paz-Artal E, Naval J, Allende LM et al. (2007). The induction of Bim expression in human T-cell blasts is dependent on nonapoptotic Fas/CD95 signaling. Blood 109: 1627–1635.

    Article  CAS  Google Scholar 

  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al. (1999). Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 96: 857–868.

    Article  CAS  Google Scholar 

  • Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME . (2001). Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 21: 952–965.

    Article  CAS  Google Scholar 

  • Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y et al. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303: 2011–2015.

    Article  CAS  Google Scholar 

  • Charvet C, Canonigo AJ, Becart S, Maurer U, Miletic AV, Swat W et al. (2006). Vav1 promotes T cell cycle progression by linking TCR/CD28 costimulation to 26 and p27kip1 expression. J Immunol 177: 5024–5031.

    Article  CAS  Google Scholar 

  • Chen J, Yusuf I, Andersen HM, Fruman DA . (2006). FOXO transcription factors cooperate with dEF1 to activate growth suppressive genes in B lymphocytes. J Immunol 176: 2711–2721.

    Article  CAS  Google Scholar 

  • Coffer PJ, Burgering BM . (2004). Forkhead-box transcription factors and their role in the immune system. Nature Rev Immunol 4: 889–899.

    Article  CAS  Google Scholar 

  • Crellin NK, Garcia RV, Levings MK . (2007). Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells. Blood 109: 2014–2022.

    Article  CAS  Google Scholar 

  • Crossley LJ . (2003). Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1. J Leuk Biol 74: 583–592.

    Article  CAS  Google Scholar 

  • Daitoku H, Hatta M, Matsuzaki H, Aratani S, Ohshima T, Miyagishi M et al. (2004). Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity. Proc Natl Acad Sci USA 101: 10042–10047.

    Article  CAS  Google Scholar 

  • De Ruiter ND, Burgering BM, Bos JL . (2001). Regulation of the forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451. Mol Cell Biol 21: 8225–8235.

    Article  CAS  Google Scholar 

  • Dijkers PF, Birkenkamp KU, Lam EW, Thomas NS, Lammers JW, Koenderman L et al. (2002). FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. J Cell Biol 156: 531–542.

    Article  CAS  Google Scholar 

  • Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL et al. (2004). FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23: 4802–4812.

    Article  CAS  Google Scholar 

  • Fabre S, Lang V, Bismuth G . (2006). PI3-kinase and the control of T cell growth and proliferation by Foxos. Bull Cancer 93: E36–E38.

    PubMed  Google Scholar 

  • Fabre S, Lang V, Harriague J, Jobart A, Unterman TG, Trautmann A et al. (2005). Stable activation of phosphatidylinositol 3-kinase in the T cell immunological synapse stimulates Akt signaling to FoxO1 nuclear exclusion and cell growth control. J Immunol 174: 4161–4171.

    Article  CAS  Google Scholar 

  • Fallarino F, Bianchi R, Orabona C, Vacca C, Belladonna ML, Fioretti MC et al. (2004). CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice. J Exp Med 200: 1051–1062.

    Article  CAS  Google Scholar 

  • Fosbrink M, Niculescu F, Rus V, Shin ML, Rus H . (2006). C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor 26. J Biol Chem 281: 19009–19018.

    Article  CAS  Google Scholar 

  • Georgiades SN, Clardy J . (2005). Total synthesis of psammaplysenes A and B, naturally occurring inhibitors of 26a nuclear export. Org Lett 7: 4091–4094.

    Article  CAS  Google Scholar 

  • Hinman RM, Bushanam JN, Nichols WA, Satterthwaite AB . (2007). B cell receptor signaling down-regulates forkhead box transcription factor class O 1 mRNA expression via phosphatidylinositol 3-kinase and Bruton's tyrosine kinase. J Immunol 178: 740–747.

    Article  CAS  Google Scholar 

  • Hu MC, Lee DF, Xia W, Golfman LS, Ou-Yang F, Yang JY et al. (2004). IkB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117: 225–237.

    Article  CAS  Google Scholar 

  • Huang H, Regan KM, Lou Z, Chen J, Tindall DJ . (2006). CDK2-dependent phosphorylation of 26 as an apoptotic response to DNA damage. Science 314: 294–297.

    Article  CAS  Google Scholar 

  • Huang H, Regan KM, Wang F, Wang D, Smith DI, van Deursen JM et al. (2005). Skp2 inhibits 26 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci USA 102: 1649–1654.

    Article  CAS  Google Scholar 

  • Hughes LB, Morrison D, Westfall AO, Tiwari HK, Alarcon GS, Conn DL et al. (2006). Genetic and Non-genetic Factors Associated with Baseline Radiographic Erosions in African-Americans with Early Rheumatoid Arthritis: Results from the CLEAR Registry (70th Annual Meeting of the American College of Rheumatology, Washington, DC). John Wiley & Sons, Hoboken, NJ, USA.

    Google Scholar 

  • Jacobsen EA, Ananieva O, Brown ML, Chang Y . (2006). Growth, differentiation, and malignant transformation of pre-B cells mediated by inducible activation of v-Abl oncogene. J Immunol 176: 6831–6838.

    Article  CAS  Google Scholar 

  • Jonsson H, Peng SL . (2005). Forkhead transcription factors in immunology. Cell Molec Life Sci 62: 397–409.

    Article  CAS  Google Scholar 

  • Jonsson H, Allen P, Peng SL . (2005). Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nature Med 11: 666–671.

    Article  CAS  Google Scholar 

  • Kau TR, Schroeder F, Ramaswamy S, Wojciechowski CL, Zhao JJ, Roberts TM et al. (2003). A chemical genetic screen identifies inhibitors of regulated nuclear export of a forkhead transcription factor in PTEN-deficient tumor cells. Cancer Cell 4: 463–476.

    Article  CAS  Google Scholar 

  • Kops GJ, Dansen TB, Polderman PE, Saarloos I, Wirtz KW, Coffer PJ et al. (2002). Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419: 316–321.

    Article  CAS  Google Scholar 

  • Lam EW, Francis RE, Petkovic M . (2006). FOXO transcription factors: key regulators of cell fate. Biochem Soc Trans 34: 722–726.

    Article  CAS  Google Scholar 

  • Lehtinen MK, Yuan Z, Boag PR, Yang Y, Villen J, Becker EB et al. (2006). A conserved MST-FOXO signaling pathway mediates oxidative-stress responses and extends life span. Cell 125: 987–1001.

    Article  CAS  Google Scholar 

  • Lin L, Hron JD, Peng SL . (2004). Regulation of NF-kB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity 21: 203–213.

    Article  CAS  Google Scholar 

  • Ludikhuize J, de Launay D, Groot D, Smeets TJ, Vinkenoog M, Sanders ME et al. (2007). Inhibition of forkhead box class O family member transcription factors in rheumatoid synovial tissue. Arthritis Rheum 56: 2180–2191.

    Article  CAS  Google Scholar 

  • Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A . (2005). Acetylation of Foxo1 alters its DNA-binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci USA 102: 11278–11283.

    Article  CAS  Google Scholar 

  • Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A . (2003). Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci USA 100: 11285–11290.

    Article  CAS  Google Scholar 

  • Medema RH, Kops GJ, Bos JL, Burgering BM . (2000). AFX-like forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404: 782–787.

    Article  CAS  Google Scholar 

  • Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W et al. (2004). Mammalian SIRT1 represses forkhead transcription factors. Cell 116: 551–563.

    Article  CAS  Google Scholar 

  • Nakae J, Cao Y, Daitoku H, Fukamizu A, Ogawa W, Yano Y et al. (2006). The LXXLL motif of murine forkhead transcription factor FoxO1 mediates Sirt1-dependent transcriptional activity. J Clin Invest 116: 2473–2483.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nemoto S, Finkel T . (2002). Redox regulation of forkhead proteins through a p66shc-dependent signaling pathway. Science 295: 2450–2452.

    Article  CAS  Google Scholar 

  • Pandiyan P, Gartner D, Soezeri O, Radbruch A, Schulze-Osthoff K, Brunner-Weinzierl MC . (2004). CD152 (CTLA-4) determines the unequal resistance of Th1 and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function. J Exp Med 199: 831–842.

    Article  CAS  Google Scholar 

  • Peng SL . (2007). Immune regulation by Foxo transcription factors. Autoimmunity 40: 462–469.

    Article  CAS  Google Scholar 

  • Plas DR, Thompson CB . (2003). Akt activation promotes degradation of tuberin and FOXO3a via the proteasome. J Biol Chem 278: 12361–12366.

    Article  CAS  Google Scholar 

  • Ramaswamy S, Nakamura N, Sansal I, Bergeron L, Sellers WR . (2002). A novel mechanism of gene regulation and tumor suppression by the transcription factor FKHR. Cancer Cell 2: 81–91.

    Article  CAS  Google Scholar 

  • Reedquist KA, Ludikhuize J, Tak PP . (2006). Phosphoinositide 3-kinase signalling and Foxo transcription factors in rheumatoid arthritis. Biochem Soc Trans 34: 727–730.

    Article  CAS  Google Scholar 

  • Rena G, Bain J, Elliott M, Cohen P . (2004). D4476, a cell-permeant inhibitor of CK1, suppresses the site-specific phosphorylation and nuclear exclusion of 26a. EMBO Rep 5: 60–65.

    Article  CAS  Google Scholar 

  • Rena G, Woods YL, Prescott AR, Peggie M, Unterman TG, Williams MR et al. (2002). Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J 21: 2263–2271.

    Article  CAS  Google Scholar 

  • Riou C, Yassine-Diab B, Van Grevenynghe J, Somogyi R, Greller LD, Gagnon D et al. (2007). Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells. J Exp Med 204: 79–91.

    Article  CAS  Google Scholar 

  • Schroeder FC, Kau TR, Silver PA, Clardy J . (2005). The psammaplysenes, specific inhibitors of 26a nuclear export. J Nat Prod 68: 574–576.

    Article  CAS  Google Scholar 

  • Sela U, Dayan M, Hershkoviz R, Cahalon L, Lider O, Mozes E . (2006). The negative regulators Foxj1 and Foxo3a are upregulated by a peptide that inhibits systemic lupus erythematosus-associated T cell responses. Eur J Immunol 36: 2971–2980.

    Article  CAS  Google Scholar 

  • So CW, Cleary ML . (2003). Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood 101: 633–639.

    Article  CAS  Google Scholar 

  • Stahl M, Dijkers PF, Kops GJ, Lens SM, Coffer PJ, Burgering BM et al. (2002). The forkhead transcription factor Foxo regulates transcription of p27Kip1 and Bim in response to IL-2. J Immunol 168: 5024–5031.

    Article  CAS  Google Scholar 

  • Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE et al. (2007). Foxos are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128: 325–339.

    Article  CAS  Google Scholar 

  • Tsuchida K, Chaki H, Takakura T, Kotsubo H, Tanaka T, Aikawa Y et al. (2006). Discovery of nonpeptidic small-molecule AP-1 inhibitors: lead hopping based on a three-dimensional pharmacophore model. J Med Chem 49: 80–91.

    Article  CAS  Google Scholar 

  • van der Heide LP, Smidt MP . (2005). Regulation of Foxo activity by CBP/p300-mediated acetylation. Trends Biochem Sci 30: 81–86.

    Article  CAS  Google Scholar 

  • van der Horst A, de Vries-Smits AM, Brenkman AB, van Triest MH, van den Broek N, Colland F et al. (2006). FOXO4 transcriptional activity is regulated by monoubiquitination and USP7/HAUSP. Nature Cell Biol 8: 1064–1073.

    Article  CAS  Google Scholar 

  • van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM . (2004). FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem 279: 28873–28879.

    Article  CAS  Google Scholar 

  • Wijchers PJ, Burbach JP, Smidt MP . (2006). In control of biology: of mice, men and Foxes. Biochem J 397: 233–246.

    Article  CAS  Google Scholar 

  • Woods YL, Rena G, Morrice N, Barthel A, Becker W, Guo S et al. (2001). The kinase DYRK1A phosphorylates the transcription factor FKHR at Ser329 in vitro, a novel in vivo phosphorylation site. Biochem J 355: 597–607.

    Article  CAS  Google Scholar 

  • Yamamura Y, Lee WL, Inoue K, Ida H, Ito Y . (2006). RUNX3 cooperates with Foxo3a to induce apoptosis in gastric cancer cells. J Biol Chem 281: 5267–5276.

    Article  CAS  Google Scholar 

  • Yang KY, Arcaroli J, Kupfner J, Pitts TM, Park JS, Strasshiem D et al. (2003). Involvement of phosphatidylinositol 3-kinase gamma in neutrophil apoptosis. Cell Signal 15: 225–233.

    Article  CAS  Google Scholar 

  • Yau CY, Wheeler JJ, Sutton KL, Hedley DW . (2005). Inhibition of integrin-linked kinase by a selective small molecule inhibitor, QLT0254, inhibits the PI3K/PKB/mTOR, Stat3, and FKHR pathways and tumor growth, and enhances gemcitabine-induced apoptosis in human orthotopic primary pancreatic cancer xenografts. Cancer Res 65: 1497–1504.

    Article  CAS  Google Scholar 

  • You H, Jang Y, You-Ten AI, Okada H, Liepa J, Wakeham A et al. (2004). p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1. Proc Natl Acad Sci USA 101: 14057–14062.

    Article  CAS  Google Scholar 

  • You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, Erlacher M et al. (2006a). FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med 203: 1657–1663.

    Article  CAS  Google Scholar 

  • You H, Yamamoto K, Mak TW . (2006b). Regulation of transactivation-independent proapoptotic activity of p53 by FOXO3a. Proc Natl Acad Sci USA 103: 9051–9056.

    Article  CAS  Google Scholar 

  • Yusuf I, Zhu X, Kharas MG, Chen J, Fruman DA . (2004). Optimal B-cell proliferation requires phosphoinositide 3-kinase-dependent inactivation of FOXO transcription factors. Blood 104: 784–787.

    Article  CAS  Google Scholar 

  • Zhuang Y, Li S, Li Y . (2006). dbNEI: a specific database for neuro-endocrine-immune interactions. Neuro Endocrinol Lett 27: 53–59.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to S L Peng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peng, S. Foxo in the immune system. Oncogene 27, 2337–2344 (2008). https://doi.org/10.1038/onc.2008.26

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.26

Keywords

This article is cited by

Search

Quick links