Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells


β-catenin is a central molecule in the Wnt pathway. Expression of a stable form of β-catenin on CD4+CD25+ regulatory T (Treg) cells resulted in a marked enhancement of survival of these cells in vitro. Furthermore, stable β-catenin–expressing CD4+CD25+ Treg cells outcompeted control Treg cells in vivo, and the number of Treg cells necessary for protection against inflammatory bowel disease could be substantially reduced when stable β-catenin–expressing CD4+CD25+ Treg cells were used instead of control Treg cells. Expression of stable β-catenin on potentially pathogenic CD4+CD25 T cells rendered these cells anergic, and the β-catenin–mediated induction of anergy occurred even in Foxp3-deficient T cells. Thus, through enhanced survival of existing regulatory T cells, and through induction of unresponsiveness in precursors of T effector cells, β-catenin stabilization has a powerful effect on the prevention of inflammatory disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: CD4+CD25+ T cells expressing stable β-catenin show enhanced survival in vitro.
Figure 2: β-catenin–transduced Treg cells show enhanced Bcl-XL and decreased Bax expression.
Figure 3: Stable β-catenin–expressing Treg cells have a competitive in vivo advantage.
Figure 4: Stable β-catenin expression induces anergy in CD4+CD25 T cells.
Figure 5: CD4+CD25 T cells expressing stable β-catenin do not induce IBD in vivo.


  1. 1

    Gregorieff, A. & Clevers, H. Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev. 19, 877–890 (2005).

    CAS  Article  Google Scholar 

  2. 2

    Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).

    CAS  Article  Google Scholar 

  3. 3

    Willert, K. & Jones, K.A. Wnt signaling: is the party in the nucleus? Genes Dev. 20, 1394–1404 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Amit, S. et al. Axin-mediated CKI phosphorylation of β-catenin at Ser 45: a molecular switch for the Wnt pathway. Genes Dev. 16, 1066–1076 (2002).

    CAS  Article  Google Scholar 

  5. 5

    Liu, C. et al. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837–847 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Jiang, J. & Struhl, G. Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature 391, 493–496 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Latres, E., Chiaur, D.S. & Pagano, M. The human F box protein β-Trcp associates with the Cul1/Skp1 complex and regulates the stability of β-catenin. Oncogene 18, 849–854 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Staal, F.J., Noort Mv, M., Strous, G.J. & Clevers, H.C. Wnt signals are transmitted through N-terminally dephosphorylated β-catenin. EMBO Rep. 3, 63–68 (2002).

    CAS  Article  Google Scholar 

  9. 9

    Curotto de Lafaille, M.A. & Lafaille, J.J. CD4+ regulatory T cells in autoimmunity and allergy. Curr. Opin. Immunol. 14, 771–778 (2002).

    CAS  Article  Google Scholar 

  10. 10

    Gavin, M. & Rudensky, A. Control of immune homeostasis by naturally arising regulatory CD4+ T cells. Curr. Opin. Immunol. 15, 690–696 (2003).

    CAS  Article  Google Scholar 

  11. 11

    Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat. Immunol. 6, 345–352 (2005).

    CAS  Article  Google Scholar 

  12. 12

    Bluestone, J.A. & Abbas, A.K. Natural versus adaptive regulatory T cells. Nat. Rev. Immunol. 3, 253–257 (2003).

    CAS  Article  Google Scholar 

  13. 13

    Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    CAS  Article  Google Scholar 

  14. 14

    Apostolou, I. & von Boehmer, H. In vivo instruction of suppressor commitment in naive T cells. J. Exp. Med. 199, 1401–1408 (2004).

    CAS  Article  Google Scholar 

  15. 15

    Curotto de Lafaille, M.A., Lino, A.C., Kutchukhidze, N. & Lafaille, J.J. CD25 T cells generate CD25+Foxp3+ regulatory T cells by peripheral expansion. J. Immunol. 173, 7259–7268 (2004).

    CAS  Article  Google Scholar 

  16. 16

    Mucida, D. et al. Oral tolerance in the absence of naturally occurring Tregs. J. Clin. Invest. 115, 1923–1933 (2005).

    CAS  Article  Google Scholar 

  17. 17

    Kretschmer, K. et al. Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219–1227 (2005).

    CAS  Article  Google Scholar 

  18. 18

    Knoechel, B., Lohr, J., Kahn, E., Bluestone, J.A. & Abbas, A.K. Sequential development of interleukin-2–dependent effector and regulatory T cells in response to endogenous systemic antigen. J. Exp. Med. 202, 1375–1386 (2005).

    CAS  Article  Google Scholar 

  19. 19

    Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003).

    CAS  Article  Google Scholar 

  20. 20

    Evan, G.I. et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69, 119–128 (1992).

    CAS  Article  Google Scholar 

  21. 21

    Maclean, K.H., Keller, U.B., Rodriguez-Galindo, C., Nilsson, J.A. & Cleveland, J.L. c-Myc augments gamma irradiation-induced apoptosis by suppressing Bcl-XL . Mol. Cell. Biol. 23, 7256–7270 (2003).

    CAS  Article  Google Scholar 

  22. 22

    Dansen, T.B., Whitfield, J., Rostker, F., Brown-Swigart, L. & Evan, G.I. Specific requirement for Bax, not Bak, in Myc-induced apoptosis and tumor suppression in vivo. J. Biol. Chem. 281, 10890–10895 (2006).

    CAS  Article  Google Scholar 

  23. 23

    Soucie, E.L. et al. Myc potentiates apoptosis by stimulating Bax activity at the mitochondria. Mol. Cell. Biol. 21, 4725–4736 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Juin, P. et al. c-Myc functionally cooperates with Bax to induce apoptosis. Mol. Cell. Biol. 22, 6158–6169 (2002).

    CAS  Article  Google Scholar 

  25. 25

    Mitchell, K.O. et al. Bax is a transcriptional target and mediator of c-myc–induced apoptosis. Cancer Res. 60, 6318–6325 (2000).

    CAS  PubMed  Google Scholar 

  26. 26

    Gavin, M.A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).

    CAS  Article  Google Scholar 

  27. 27

    Powrie, F., Carlino, J., Leach, M.W., Mauze, S. & Coffman, R.L. A critical role for transforming growth factor-β but not interleukin 4 in the suppression of T helper type 1–mediated colitis by CD45RBlow CD4+ T cells. J. Exp. Med. 183, 2669–2674 (1996).

    CAS  Article  Google Scholar 

  28. 28

    Shen, S. et al. Control of homeostatic proliferation by regulatory T cells. J. Clin. Invest. 115, 3517–3526 (2005).

    CAS  Article  Google Scholar 

  29. 29

    Curotto de Lafaille, M.A. et al. Hyper immunoglobulin E response in mice with monoclonal populations of B and T lymphocytes. J. Exp. Med. 194, 1349–1359 (2001).

    CAS  Article  Google Scholar 

  30. 30

    Gounari, F. et al. Somatic activation of β-catenin bypasses pre-TCR signaling and TCR selection in thymocyte development. Nat. Immunol. 2, 863–869 (2001).

    CAS  Article  Google Scholar 

  31. 31

    Ioannidis, V., Beermann, F., Clevers, H. & Held, W. The β-catenin–TCF-1 pathway ensures CD4+CD8+ thymocyte survival. Nat. Immunol. 2, 691–697 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Ohteki, T. et al. Negative regulation of T cell proliferation and interleukin 2 production by the serine threonine kinase GSK-3. J. Exp. Med. 192, 99–104 (2000).

    CAS  Article  Google Scholar 

  33. 33

    Staal, F.J. et al. Wnt signaling is required for thymocyte development and activates Tcf-1 mediated transcription. Eur. J. Immunol. 31, 285–293 (2001).

    CAS  Article  Google Scholar 

  34. 34

    Mulroy, T., Xu, Y. & Sen, J.M. β-catenin expression enhances generation of mature thymocytes. Int. Immunol. 15, 1485–1494 (2003).

    CAS  Article  Google Scholar 

  35. 35

    Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    CAS  Article  Google Scholar 

  36. 36

    Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    CAS  Article  Google Scholar 

  37. 37

    Lombardi, G., Sidhu, S., Batchelor, R. & Lechler, R. Anergic T cells as suppressor cells in vitro. Science 264, 1587–1589 (1994).

    CAS  Article  Google Scholar 

  38. 38

    Lin, W. et al. Regulatory T cell development in the absence of functional Foxp3. Nat. Immunol. 8, 359–368 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375–387 (2006).

    CAS  Article  Google Scholar 

Download references


We thank D. Littman for comments, A. Rudensky for discussing unpublished data, M. Leung for the effector cytokine data in Supplementary Figure 3, H. Huo for assistance with the shRNA constructs and the transduction of TCR transgenic T cells, and T. Reya (Duke University Medical Center, Durham, NC) for the stable β-catenin and empty control vectors. S.S. is a recipient of a postdoctoral fellowship from the Juvenile Diabetes Research Foundation. A.C.L. is a recipient of a predoctoral fellowship from Fundacao para a Ciencia e a Tecnologia (FCT, Portugal). Work in J.J.L.'s laboratory is funded by the National Institutes of Health/NIAID, and the National Multiple Sclerosis Society.

Author information




Y.D. was involved in the execution of all experiments and the preparation of the manuscript. S.S. contributed to some of the in vivo experiments, A.C.L. contributed to some of the in vitro experiments and M.A.C.L. contributed to the experiments with the T/B monoclonal and T/B monoclonal Scurfy mouse lines. J.J.L. supervised the project and prepared the manuscript.

Corresponding author

Correspondence to Juan J Lafaille.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1–4 and Supplementary Table 1 (PDF 333 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ding, Y., Shen, S., Lino, A. et al. Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nat Med 14, 162–169 (2008).

Download citation

Further reading


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing