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Ellen N Kersh, David R Fitzpatrick, Kaja Murali-Krishna, John Shires, Samuel H Speck, Jeremy M Boss, Rafi Ahmed, Rapid Demethylation of the IFN-γ Gene Occurs in Memory but Not Naive CD8 T Cells, The Journal of Immunology, Volume 176, Issue 7, April 2006, Pages 4083–4093, https://doi.org/10.4049/jimmunol.176.7.4083
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Abstract
DNA methylation is an epigenetic mechanism of gene regulation. We have determined that specific modifications in DNA methylation at the IFN-γ locus occur during memory CD8 T cell differentiation in vivo. Expression of the antiviral cytokine IFN-γ in CD8 T cells is highly developmental stage specific. Most naive cells must divide before they express IFN-γ, while memory cells vigorously express IFN-γ before cell division. Ag-specific CD8 T cells were obtained during viral infection of mice and examined directly ex vivo. Naive cells had an IFN-γ locus with extensive methylation at three specific CpG sites. An inhibitor of methylation increased the amount of IFN-γ in naive cells, indicating that methylation contributes to the slow and meager production of IFN-γ. Effectors were unmethylated and produced large amounts of IFN-γ. Interestingly, while memory cells were also able to produce large amounts of IFN-γ, the gene was partially methylated at the three CpG sites. Within 5 h of antigenic stimulation, however, the gene was rapidly demethylated in memory cells. This was independent of DNA synthesis and cell division, suggesting a yet unidentified demethylase. Rapid demethylation of the IFN-γ promoter by an enzymatic factor only in memory cells would be a novel mechanism of differential gene regulation. This differentiation stage-specific mechanism reflects a basic immunologic principle: naive cells need to expand before becoming an effective defense factor, whereas memory cells with already increased precursor frequency can rapidly mount effector functions to eliminate reinfecting pathogens in a strictly Ag-dependent fashion.
