Abstract
The transcription factor Foxp3 has an indispensable role in establishing stable transcriptional and functional programs of regulatory T cells (Treg cells). Loss of Foxp3 expression in mature Treg cells results in a failure of suppressor function, yet the molecular mechanisms that ensure steady, heritable Foxp3 expression in the Treg cell lineage remain unknown. Using Treg cell–specific gene targeting, we found that complexes of the transcription factors Runx and CBFβ were required for maintenance of Foxp3 mRNA and protein expression in Treg cells. Consequently, mice lacking CBFβb exclusively in the Treg cell lineage had a moderate lymphoproliferative syndrome. Thus, Runx-CBFβ complexes maintain stable high expression of Foxp3 and serve as an essential determinant of Treg cell lineage stability.
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Acknowledgements
We thank M. Tone (University of Pennsylvania) for the reporter construct containing the Foxp3 promoter; K. Forbush, T. Chu and L. Karpik for managing the mouse colony; and I. Taniuchi, Y. Tone and M. Tone for advice. Supported by the National Institutes of Health (A.Y.R.), the Arthritis Foundation (D.R.), the Leukemia and Lymphoma Society (T.E.), the Helen and Martin Kimmel Center for Stem Cell Biology (M.M.W.C.) and the Howard Hughes Medical Institute (A.Y.R. and D.R.L).
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D.R. designed and did experiments, analyzed the data and cowrote the manuscript with A.Y.R.; T.E., M.M.W.C. and D.R.L. generated and analyzed Runx1fl/flFoxp3YFP-Cre mice and Cbfbfl/flCD4-Cre+ mice; P.T. did histopathology analysis; and A.Y.R. designed experiments with D.R., analyzed the data and cowrote the manuscript with D.R.
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Rudra, D., Egawa, T., Chong, M. et al. Runx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat Immunol 10, 1170–1177 (2009). https://doi.org/10.1038/ni.1795
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DOI: https://doi.org/10.1038/ni.1795
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