title: T cell receptor (TCR) and transforming growth factor β (TGF-β) signaling converge on DNA (cytosine-5)-methyltransferase to control forkhead box protein 3 (foxp3) locus methylation and inducible regulatory T cell differentiation.
abstract: Naïve T cells can be induced to differentiate into Foxp3(+) regulatory T cells (iTregs) upon suboptimal T cell receptor (TCR) stimulus or TCR stimulus in conjunction with TGF-β signaling; however, we do not fully understand how these signals coordinately control foxp3 expression. Here, we show that strong TCR activation, in terms of both duration and ligand affinity, causes the accumulation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) and DNMT3b and their specific enrichment at the foxp3 locus, which leads to increased CpG methylation and inhibits foxp3 transcription. During this process the augmentation of DNMT1 is regulated through at least two post-transcriptional mechanisms; that is, strong TCR signal inactivates GSK3β to rescue DNMT1 protein from proteasomal degradation, and strong TCR signal suppresses miR-148a to derepress DNMT1 mRNA translation. Meanwhile, TGF-β signaling antagonizes DNMT1 accumulation via activation of p38 MAP kinase. Thus, independent of transcription factor activation, TCR and TGF-β signals converge on DNMT1 to modulate the expression of foxp3 epigenetically, which marks mother cell iTreg lineage choice within the genome of differentiating daughter cells.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Chaoran
authors.initials: C
authors.lastname: Li
authors.forename: Peter J R
authors.initials: PJ
authors.lastname: Ebert
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D044127:Epigenesis, Genetic; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D035683:MicroRNAs; C554644:Mirn148 microRNA, mouse; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D004248:DNA (Cytosine-5-)-Methyltransferases
keywords: DNA Methyltransferase; Epigenetics; MicroRNA; Protein Degradation; Regulatory T Cell Differentiation; TCR Signaling; Transforming Growth Factor β (TGFβ); foxp3; miR-148a