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Gene Occurs in Memory but Not Naive CD8 T Cells1
* Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
Amgen, Seattle, WA 98119; and
Department of Immunology, University of Washington, Seattle, WA 98195
DNA methylation is an epigenetic mechanism of gene regulation. We have determined that specific modifications in DNA methylation at the IFN-
locus occur during memory CD8 T cell differentiation in vivo. Expression of the antiviral cytokine IFN- in CD8 T cells is highly developmental stage specific. Most naive cells must divide before they express IFN-, while memory cells vigorously express IFN- 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- locus with extensive methylation at three specific CpG sites. An inhibitor of methylation increased the amount of IFN- in naive cells, indicating that methylation contributes to the slow and meager production of IFN-. Effectors were unmethylated and produced large amounts of IFN-. Interestingly, while memory cells were also able to produce large amounts of IFN-, 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- 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.
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