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Loss of methylation at the IFNG promoter and CNS-1 associates with the development of functional IFN-γ memory in human CD4(+) T lymphocytes

Item Type:Article
Title:Loss of methylation at the IFNG promoter and CNS-1 associates with the development of functional IFN-γ memory in human CD4(+) T lymphocytes
Creators Name:Dong, J. and Chang, H.D. and Ivascu, C. and Qian, Y. and Rezai, S. and Okhrimenko, A. and Cosmi, L. and Maggi, L. and Eckhardt, F. and Wu, P. and Sieper, J. and Alexander, T. and Annunziato, F. and Gossen, M. and Li, J. and Radbruch, A. and Thiel, A.
Abstract:Cytokine memory for IFN-{gamma} 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 hours, and this process was independent of cell proliferation and DNA synthesis. Using an IFN-{gamma} capture assay, we found early IFN-{gamma}-producing cells from two-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-{gamma}-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-{gamma} memory in effector/memory Th1 cells characterized by hypomethylation at the IFNG promoter and CNS-1.
Keywords:Demethylation, Human IFNG Gene, IFN-gamma Cytokine Memory, Promoter and CNS-1, Th1 Cell Differentiation
Source:European Journal of Immunology
ISSN:0014-2980
Publisher:Wiley (U.S.A.)
Volume:43
Number:3
Page Range:793-804
Date:March 2013
Official Publication:https://doi.org/10.1002/eji.201242858
PubMed:View item in PubMed

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