CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation.
Regulatory T cells (T reg cells) are a population of CD4+ T cells that limit immune responses. FoxP3 is a master control transcription factor for development and function of these cells, but its regulation is poorly understood. We have identified a T cell receptor-responsive enhancer in the FoxP3 first intron that is dependent on a cyclic-AMP response element binding protein (CREB)/activating transcription factor (ATF) site overlapping a CpG island. Methylation of this island inversely correlates with CREB binding and FoxP3 expression. Interestingly, transforming growth factor-beta, which induces T reg cell formation, decreases methylation of the CpG island and increases FoxP3 expression. Similarly, inhibiting methylation with 5-azacytidine or knocking down the DNA methyltransferase Dnmt1 also induces FoxP3 expression. Conversely, methylation of the CpG island, which decreases CREB binding or expression of dominant-negative CREB, decreases FoxP3 gene expression. Thus, T cell receptor-induced FoxP3 expression in T reg cells is controlled both by sequence-specific binding of CREB/ATF and by DNA methylation of a CpG island.
Kim
Hyoung-Pyo
HP
Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Leonard
Warren J
WJ
D051696:Activating Transcription Factors / Q000378:metabolism*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019175:DNA Methylation; D015226:Dinucleoside Phosphates / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D007668:Kidney; D016086:Lentivirus / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014162:Transfection
D051696:Activating Transcription Factors; D001798:Blood Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D015226:Dinucleoside Phosphates; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C015772:CpG dinucleotide