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

Abstract

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.

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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.

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Acknowledgements

We thank D. Littman for comments, A. Rudensky for discussing unpublished data, M. Leung for the effector cytokine data in Supplementary Figure 3, H. Huo for assistance with the shRNA constructs and the transduction of TCR transgenic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.

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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.

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Correspondence to Juan J Lafaille.

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

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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). https://doi.org/10.1038/nm1707

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