Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis

Abstract

Abstract Maintenance of memory CD8 T cell quantity and quality through antigen-independent homeostatic proliferation is vital for sustaining long-lived T cell-mediated immunity, yet the underlying mechanisms that preserve memory T cell functions during homeostasis remain largely unexplored. Here we show that preservation of effector-potential among human memory CD8 T cells during in vitro and in vivo homeostasis is coupled to maintenance of memory-associated DNA methylation programs. Whole-genome bisulfite sequencing of primary human naïve, short-lived effector memory (Tem), and longer-lived central memory (Tcm) and stem cell memory (Tscm) CD8 T cells identified demethylated promoters of effector molecules that are poised for rapid expression among all memory cell subsets. Effector-loci demethylation was heritably preserved during IL-7 and IL-15 mediated in vitro cell proliferation. In contrast to the effector-potential, antigen-independent proliferation induced a phenotypic conversion of Tcm and Tscm memory cells into Tem cells that was coupled to increased methylation of the CCR7 locus. Furthermore, in vivo proliferation of haploidentical donor memory CD8 T cells in lymhodepleted recipients resulted in a similar preservation of effector-associated methylation programs while enriching for Tem-associated programs. These data demonstrate that long-lived human memory CD8 T cells retain the ability to undergo antigen-independent epigenetic reprogramming during their developmental conversion into other memory subsets while at the same time preserving the poised effector state utilized by all memory T cells.