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

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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., Chang, H.D., Ivascu, C., Qian, Y., Rezai, S., Okhrimenko, A., Cosmi, L., Maggi, L., Eckhardt, F., Wu, P., Sieper, J., Alexander, T., Annunziato, F., Gossen, M., Li, J., 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
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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