Unique abilities of human memory T cell subsets are associated with both specialized gene expression modules and epigenetic priming.

Abstract

Memory T cells are a diverse set of cells that respond to immunologic challenge more quickly and with greater efficacy than their naïve counterparts. Their potential in the resting and stimulated state has not been explored for each of the subsets. To define their capabilities, RNA-seq and ATAC-seq data assessing the transcriptome and chromatin accessibility potential of both resting and activated human memory T cells was analyzed. Clustering gene expression modules identified a core set of genes highly expressed in both resting central memory and effector memory cells (but not in naïve or terminally differentiated effector cells). Memory subsets also expressed unique gene modules enabling specialized functions such as cell cytotoxicity, migration, or self-renewal. Subset differences in gene expression were reflected in differentiated chromatin accessibility and enhanced variation around binding motifs for key T cell differentiation transcription factors such as Tbet, EOMES, and LEF1. Upon activation memory T cells showed substantial rapid upregulation of genes including cytokines which were absent in activated naïve T cells. These differences in gene expression from naïve T cells were often preceded by areas of open chromatin in a resting memory state, suggesting mechanisms of epigenetic priming for rapid recall or augmentation of effector T cell function in memory. In summary, memory T cell subsets are distinct in both resting gene expression functionalities and differentiated epigenetic landscape—both of which enable unique, rapid, and effective response to antigen.