Cutting edge: TCR stimulation is sufficient for induction of Foxp3 expression in the absence of DNA methyltransferase 1.
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.
Josefowicz
Steven Z
SZ
Department of Immunology, University of Washington, Seattle, WA 98195, USA.
Wilson
Christopher B
CB
Rudensky
Alexander Y
AY
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D053773:Transforming Growth Factor beta1; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse