Abstract
Appropriate expression of IL-2 plays a central role during the priming and differentiation of T cells. A tight balance between IL-2 and the effector cytokine IL-17A is essential for immune homeostasis. Epigenetic mechanisms have been documented as a key component of cytokine regulation during lineage commitment. The molecular mechanisms that induce chromatin remodeling are less well understood. We investigated epigenetic regulators that mediate the diametric expression of IL-2 and IL-17A in naive, central memory, and effector memory CD4(+) T cells. We demonstrate that cAMP response modulator (CREM)α contributes to epigenetic remodeling of IL2 in effector memory T cells through the recruitment of DNMT3a. CREMα also reduces CpG-DNA methylation of the IL17A promoter. CREMα expression is regulated at the epigenetic level by CpG-DNA methylation, which allows increased CREMα expression in effector memory CD4(+) T cells. T cells from patients with systemic lupus erythematosus (SLE) express increased levels of CREMα and exhibit a phenotype that is similar to effector memory CD4(+) T cells with epigenetically predetermined expression patterns of IL-2 and IL-17A. We conclude that CREMα mediates epigenetic remodeling of the IL2 and IL17A gene during T-cell differentiation in favor of effector memory T cells in health and disease.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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Cell Lineage / immunology
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Cells, Cultured
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CpG Islands / genetics
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Cyclic AMP Response Element Modulator / genetics
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Cyclic AMP Response Element Modulator / immunology*
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Cyclic AMP Response Element Modulator / metabolism
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / immunology
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation
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DNA Methyltransferase 3A
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Flow Cytometry
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Gene Expression
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HEK293 Cells
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Humans
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Immunologic Memory / immunology
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Interleukin-17 / genetics
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Interleukin-17 / immunology*
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Interleukin-17 / metabolism
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Interleukin-2 / genetics
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Interleukin-2 / immunology*
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Interleukin-2 / metabolism
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Jurkat Cells
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Lupus Erythematosus, Systemic / genetics
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Lupus Erythematosus, Systemic / immunology*
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Lupus Erythematosus, Systemic / metabolism
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Promoter Regions, Genetic / genetics
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Protein Binding
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / pathology
Substances
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DNMT3A protein, human
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Interleukin-17
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Interleukin-2
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Cyclic AMP Response Element Modulator
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A