Foxo Transcription Factors Control Regulatory T Cell Development and Function

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2010 Dec 21

PMID 21167754

Citations 251

Authors

Yann M Kerdiles

Erica L Stone

Daniel R Beisner

Daniel L Beisner

Maureen A McGargill

Irene L Chen

Christian Stockmann

Carol D Katayama

Stephen M Hedrick

Affiliations

Soon will be listed here.

Abstract

Foxo transcription factors integrate extrinsic signals to regulate cell division, differentiation and survival, and specific functions of lymphoid and myeloid cells. Here, we showed the absence of Foxo1 severely curtailed the development of Foxp3(+) regulatory T (Treg) cells and those that developed were nonfunctional in vivo. The loss of function included diminished CTLA-4 receptor expression as the Ctla4 gene was a direct target of Foxo1. T cell-specific loss of Foxo1 resulted in exocrine pancreatitis, hind limb paralysis, multiorgan lymphocyte infiltration, anti-nuclear antibodies and expanded germinal centers. Foxo-mediated control over Treg cell specification was further revealed by the inability of TGF-β cytokine to suppress T-bet transcription factor in the absence of Foxo1, resulting in IFN-γ secretion. In addition, the absence of Foxo3 exacerbated the effects of the loss of Foxo1. Thus, Foxo transcription factors guide the contingencies of T cell differentiation and the specific functions of effector cell populations.

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References

McHeyzer-Williams L, Pelletier N, Mark L, Fazilleau N, McHeyzer-Williams M . Follicular helper T cells as cognate regulators of B cell immunity. Curr Opin Immunol. 2009; 21(3):266-73. PMC: 2731669. DOI: 10.1016/j.coi.2009.05.010. View

Shiow L, Rosen D, Brdickova N, Xu Y, An J, Lanier L . CD69 acts downstream of interferon-alpha/beta to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature. 2006; 440(7083):540-4. DOI: 10.1038/nature04606. View

Ise W, Kohyama M, Nutsch K, Lee H, Suri A, Unanue E . CTLA-4 suppresses the pathogenicity of self antigen-specific T cells by cell-intrinsic and cell-extrinsic mechanisms. Nat Immunol. 2009; 11(2):129-35. PMC: 3235641. DOI: 10.1038/ni.1835. View

Sugimoto N, Oida T, Hirota K, Nakamura K, Nomura T, Uchiyama T . Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int Immunol. 2006; 18(8):1197-209. DOI: 10.1093/intimm/dxl060. View

Seoane J, Le H, Shen L, Anderson S, Massague J . Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation. Cell. 2004; 117(2):211-23. DOI: 10.1016/s0092-8674(04)00298-3. View

Friedline R, Brown D, Nguyen H, Kornfeld H, Lee J, Zhang Y . CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J Exp Med. 2009; 206(2):421-34. PMC: 2646578. DOI: 10.1084/jem.20081811. View

Lin J, Martin S, Xia L, Gorham J . TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol. 2005; 174(10):5950-8. DOI: 10.4049/jimmunol.174.10.5950. View

von Boehmer H, Melchers F . Checkpoints in lymphocyte development and autoimmune disease. Nat Immunol. 2009; 11(1):14-20. DOI: 10.1038/ni.1794. View

Drennan M, Elewaut D, Hogquist K . Thymic emigration: sphingosine-1-phosphate receptor-1-dependent models and beyond. Eur J Immunol. 2009; 39(4):925-30. DOI: 10.1002/eji.200838912. View

10.

Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M . T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A. 2008; 105(22):7797-802. PMC: 2409380. DOI: 10.1073/pnas.0800928105. View

11.

Laouar Y, Town T, Jeng D, Tran E, Wan Y, Kuchroo V . TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2008; 105(31):10865-70. PMC: 2504840. DOI: 10.1073/pnas.0805058105. View

12.

Perkins D, Wang Z, Donovan C, He H, Mark D, Guan G . Regulation of CTLA-4 expression during T cell activation. J Immunol. 1996; 156(11):4154-9. View

13.

Yu Q, Erman B, Park J, Feigenbaum L, Singer A . IL-7 receptor signals inhibit expression of transcription factors TCF-1, LEF-1, and RORgammat: impact on thymocyte development. J Exp Med. 2004; 200(6):797-803. PMC: 2211960. DOI: 10.1084/jem.20032183. View

14.

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

15.

Dutz J, Ong C, Marth J, Teh H . Distinct differentiative stages of CD4+CD8+ thymocyte development defined by the lack of coreceptor binding in positive selection. J Immunol. 1995; 154(6):2588-99. View

16.

Paik J, Kollipara R, Chu G, Ji H, Xiao Y, Ding Z . FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell. 2007; 128(2):309-23. PMC: 1855089. DOI: 10.1016/j.cell.2006.12.029. View

17.

Wing K, Sakaguchi S . Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol. 2009; 11(1):7-13. DOI: 10.1038/ni.1818. View

18.

Julien L, Carriere A, Moreau J, Roux P . mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol. 2009; 30(4):908-21. PMC: 2815569. DOI: 10.1128/MCB.00601-09. View

19.

Crellin N, Garcia R, Levings M . Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells. Blood. 2006; 109(5):2014-22. DOI: 10.1182/blood-2006-07-035279. View

20.

Mabrouk I, Buart S, Hasmim M, Michiels C, Connault E, Opolon P . Prevention of autoimmunity and control of recall response to exogenous antigen by Fas death receptor ligand expression on T cells. Immunity. 2008; 29(6):922-33. DOI: 10.1016/j.immuni.2008.10.007. View