title: cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus.
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.
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. chedrich@bidmc.harvard.edu
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hedrich
authors.forename: Jose C
authors.initials: JC
authors.lastname: Crispin
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: Christina
authors.initials: C
authors.lastname: Ioannidis
authors.forename: Sokratis A
authors.initials: SA
authors.lastname: Apostolidis
authors.forename: Mindy S
authors.initials: MS
authors.lastname: Lo
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019070:Cell Lineage / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D005434:Flow Cytometry; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: C000717967:DNMT3A protein, human; D020381:Interleukin-17; D007376:Interleukin-2; D051786:Cyclic AMP Response Element Modulator; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A