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Cutting Edge: TCR Stimulation Is Sufficient for Induction of Foxp3 Expression in the Absence of DNA Methyltransferase 1¹

Steven Z. Josefowicz^*,, Christopher B. Wilson^* and Alexander Y. Rudensky^2,*,

^* Department of Immunology, University of Washington, Seattle, WA 98195; and Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065

TCR signaling is important for regulatory T cell (Tr) development. Using a genetic model of DNA methyltransferase 1 (Dnmt1) deficiency, we observed highly efficient Foxp3 induction following TCR stimulation, suggesting a dominant role for TCR signaling in Foxp3 induction. In the absence of Dnmt1, Foxp3 induction in thymic and peripheral Foxp3-negative T cells was maximized upon TCR engagement, and the provision of TGF-β was dispensable for Foxp3 expression. In addition, CD4-Cre x dnmt1^fl/fl mice harbored sizeable thymic and peripheral populations of CD8⁺Foxp3⁺ cells, suggesting that Dnmt1 activity is required for restricting Foxp3 expression to the CD4 T cell lineage. Our results suggest that the TCR signal is sufficient for transcriptional activation of Foxp3 in the absence of maintenance DNA methylation and that TGF-β facilitates Foxp3 induction in part by opposing cell cycle-dependent Dnmt1 recruitment, leading to locus inactivation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (to A.Y.R. and C.B.W.). S.Z.J. is supported by a predoctoral training grant from the Cancer Research Institute. A.Y.R. is a Howard Hughes Medical Institute investigator.

² Address correspondence and reprint requests to Dr. Alexander Y. Rudensky, Howard Hughes Medical Institute and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065. E-mail address: rudenska{at}mskcc.org

³ Abbreviations used in this paper: Tr, regulatory T cell; 5-aza, 5-aza-deoxycytidine; Dnmt, DNA methyltransferase; SP, single positive.

⁴ The online version of this article contains supplemental material.

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