Cutting edge: TCR stimulation is sufficient for induction of Foxp3 expression in the absence of DNA methyltransferase 1

J Immunol. 2009 Jun 1;182(11):6648-52. doi: 10.4049/jimmunol.0803320.


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-beta 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-beta facilitates Foxp3 induction in part by opposing cell cycle-dependent Dnmt1 recruitment, leading to locus inactivation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / metabolism
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / deficiency*
  • Forkhead Transcription Factors / genetics*
  • Lymphocyte Count
  • Mice
  • Mice, Knockout
  • Receptors, Antigen, T-Cell / metabolism*
  • Transcriptional Activation / immunology*
  • Transforming Growth Factor beta1 / physiology*


  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Antigen, T-Cell
  • Transforming Growth Factor beta1
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • Dnmt1 protein, mouse