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Common Features of the DNA Methylation Landscape of Human Naïve and Memory CD4, CD8 T Cells and B Cells

Epigenetic mechanisms including DNA methylation are critical drivers of immune cell lineage differentiation and activation. However, there has been limited coordinated investigation of common pathways in distinct cell types for immunological processes such as immune memory.  Further, it remains unclear if the genesis of memory in both CD4 and CD8 lineages proceeds via a linear course of differentiation or progresses in a circular ‘on-off-on’ sequence, which is epigenetically driven. Here, we scanned genome-wide differences in DNA methylation among CD4 and CD8 naive and memory cells states and combined this data with similar data on naive and memory B cell states. Our findings, overall, are consistent with the literature describing the DNA methylome as a major driver of individual central and effector T cell memory states as well as in memory B cells. We observed unusually large differences in DNA methylation in thousands of CpG sites in hundreds of genes associated with the development of memory in each lineage, contributing considerably to our knowledge of the loci regulated during lymphocyte memory generation. Our data similarly describe considerable overlap in genes with altered DNA methylation in the T cell lineage, with primarily a loss of DNA methylation in over 125,000 CpGs significantly associated with the generation of central memory in both CD4 and CD8 cells Furthermore, our analyses revealed specific CpG dinucleotides in both CD4 and CD8 cells whose methylation pattern is consistent with the circular model of memory generation. Finally, as evidence of common pathways in the generation of immune memory we highlight 22 gene loci, including several within the promoter region of the AIM2 gene, with dramatically altered DNA methylation in all three memory lineages.