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Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression

Nature volume 445, pages 766–770 (2007)Cite this article

Abstract

The naturally occurring regulatory T cell (Tr) is the pivotal cell type that maintains self-tolerance and exerts active immune suppression. The development and function of Tr cells is controlled by Foxp3 (refs 1, 2), a lack of which results in loss of Tr cells and massive multi-organ autoimmunity in scurfy mice and IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) patients3,4. It is generally thought that, through a binary mechanism, Foxp3 expression serves as an on-and-off switch to regulate positively the physiology of Tr cells; however, emerging evidence associates decreased Foxp3 expression in Tr cells with various immune disorders5,6,7. We hypothesized that Foxp3 regulates Tr cell development and function in a dose-dependent, non-binary manner, and that decreased Foxp3 expression can cause immune disease. Here, by generating a mouse model in which endogenous Foxp3 gene expression is attenuated in Tr cells, we show that decreased Foxp3 expression results in the development of an aggressive autoimmune syndrome similar to that of scurfy mice, but does not affect thymic development, homeostatic expansion/maintenance or transforming-growth-factor-β-induced de novo generation of Foxp3-expressing cells. The immune-suppressive activities of T cells with attenuated Foxp3 expression were nearly abolished in vitro and in vivo, whereas their anergic properties in vitro were maintained. This was accompanied by decreased expression of Tr cell ‘signature genes’. Notably, T cells expressing decreased Foxp3 preferentially became T-helper 2 (Th2)-type effectors even in a Th1-polarizing environment. These cells instructed Th2 differentiation of conventional T cells, which contributed to the immune diseases observed in these mice. Thus, decreased Foxp3 expression causes immune disease by subverting the suppressive function of Tr cells and converting Tr cells into effector cells; these findings are important for understanding the regulation of Tr cell function and the aetiology of various human immune diseases.

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Figure 1: Attenuated Foxp3 expression in T r cells results in an aggressive autoimmune syndrome and altered surface properties of T r cells.
Figure 2: Thymic development, homeostatic expansion/maintenance and TGF-β-induced de novo generation of T r cells are normal when Foxp3 expression is decreased.
Figure 3: Attenuation of Foxp3 expression abrogated the immune-suppressive but not hypoproliferative activities of T r cells.
Figure 4: T r cells converted into T h 2 effector cells owing to decreased Foxp3 expression.

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Acknowledgements

This research is supported by the NIH, American Diabetes Association and Howard Hughes Medical Institute. R.A.F. is an investigator of the Howard Hughes Medical Institute. Y.Y.W. is supported by a postdoctoral fellowship from the Cancer Research Institute. We thank L. Evangelisti, C. Hughes and J. Stein for assisting with the generation of FILIG mice. We are grateful to E. Eynon and L. Zenewicz for critical reading and helpful comments. We also thank F. Manzo and R. Champion for secretarial assistance.

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Authors and Affiliations

  1. Section of Immunobiology, Yale University School of Medicine, 300 Cedar Street, and,

    Yisong Y. Wan & Richard A. Flavell

  2. Howard Hughes Medical Institute, New Haven, Connecticut 06520, USA,

    Richard A. Flavell

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  1. Yisong Y. Wan
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  2. Richard A. Flavell
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Correspondence to Richard A. Flavell.

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This file contains Supplementary Methods with more detailed description of experimental procedures described in the manuscript and Supplementary Figures S1-S10. (PDF 679 kb)

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Wan, Y., Flavell, R. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445, 766–770 (2007). https://doi.org/10.1038/nature05479

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