title: Loss of methylation at the IFNG promoter and CNS-1 is associated with the development of functional IFN-γ memory in human CD4(+) T lymphocytes.
abstract: Cytokine memory for IFN-γ production by effector/memory Th1 cells plays a key role in both protective and pathological immune responses. To understand the epigenetic mechanism determining the ontogeny of effector/memory Th1 cells characterized by stable effector functions, we identified a T-cell-specific methylation pattern at the IFNG promoter and CNS-1 in ex vivo effector/memory Th1 cells, and investigated methylation dynamics of these regions during the development of effector/memory Th1 cells. During Th1 differentiation, demethylation occurred at both the promoter and CNS-1 regions of IFNG as early as 16 h, and this process was independent of cell proliferation and DNA synthesis. Using an IFN-γ capture assay, we found early IFN-γ-producing cells from 2-day differentiating cultures acquired "permissive" levels of demethylation and developed into effector/memory Th1 cells undergoing progressive demethylation at the IFNG promoter and CNS-1 when induced by IL-12. Methylation levels of these regions in effector/memory Th1 cells of peripheral blood from rheumatoid arthritis patients correlated inversely with reduced frequencies of IFN-γ-producers, coincident with recruitment of effector/memory Th1 cells to the site of inflammation. Thus, after termination of TCR stimulation, IL-12 signaling potentiates the stable functional IFN-γ memory in effector/memory Th1 cells characterized by hypomethylation at the IFNG promoter and CNS-1.
authors.affiliation: Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany. dong@drfz.de
authors.forename: Jun
authors.initials: J
authors.lastname: Dong
authors.forename: Hyun-Dong
authors.initials: HD
authors.lastname: Chang
authors.forename: Claudia
authors.initials: C
authors.lastname: Ivascu
authors.forename: Yu
authors.initials: Y
authors.lastname: Qian
authors.forename: Soheila
authors.initials: S
authors.lastname: Rezai
authors.forename: Anna
authors.initials: A
authors.lastname: Okhrimenko
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cosmi
authors.forename: Laura
authors.initials: L
authors.lastname: Maggi
authors.forename: Florian
authors.initials: F
authors.lastname: Eckhardt
authors.forename: Peihua
authors.initials: P
authors.lastname: Wu
authors.forename: Joachim
authors.initials: J
authors.lastname: Sieper
authors.forename: Tobias
authors.initials: T
authors.lastname: Alexander
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
authors.forename: Manfred
authors.initials: M
authors.lastname: Gossen
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.forename: Andreas
authors.initials: A
authors.lastname: Thiel
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma