A dynamic (epi)genomic landscape of CD8+ T cell differentiation drives cell-fate decisions

Abstract

Abstract Long-lived memory CD8+ cytotoxic T lymphocytes (CTLs) are a critical component of long-term protective immunity against intracellular pathogens following infection or vaccination. During many acute viral infections, memory CD8 T cells arise from a heterogeneous pool of CTLs that contains terminal effector (TE) cells, which are highly-functional terminally differentiated CTLs that subsequently undergo programmed contraction, and memory precursor (MP) cells, which are less differentiated effector cells that have the greatest potential to persist and seed the memory T cell pool. How these effector CTLs adopt these distinct cell fates is an important question. Several key transcription factors (TFs) have been discovered that regulate the development of these two effector CTL subsets and promote the acquisition of their unique gene signatures, but it is unclear how the epigenome contributes to the development of terminally differentiated TE and mulitpotent MP cells. To understand this question, we are profiling RNA expression, histone modifications, and DNA accessibility to dissect the (epi)genomic network throughout the early CTL response to characterize the genetic networks controlling TE and MP cell differentiation during LCMV infection. Specifically, we are focusing on how changes in enhancer utilization and chromatin remodeling are regulated by key TFs, such as T-bet and ZEB2, in controlling the expression of target genes that regulate effector cell fates. This work will provide greater insight into how T cell memory forms after infection and vaccination, which could inform future T cell based vaccine strategies to improve immunity against foreign pathogens.