Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8 + T Cell Terminal Differentiation and Loss of Multipotency

Abstract

SUMMARY Understanding immunological memory formation depends on elucidating how multipotent memory precursor (MP) cells maintain developmental plasticity and longevity to provide long-term immunity while other effector cells develop into terminally differentiated effector (TE) cells with limited survival. Profiling active (H3K27ac) and repressed (H3K27me3) chromatin in naïve, MP and TE CD8+ T cells during viral infection revealed increased H3K27me3 deposition at numerous pro-memory and pro-survival genes in TE relative to MP cells, indicative of fate restriction, but permissive chromatin at both pro-memory and pro–effector genes in MP cells, indicative of multipotency. Polycomb repressive complex 2-deficiency impaired clonal expansion and TE cell differentiation, but minimally impacted CD8+ memory T cell maturation. Abundant H3K27me3 deposition at pro-memory genes occurred late during TE cell development, likely from diminished transcription factor FOXO1 expression. These results outline a temporal model for loss of memory cell potential through selective epigenetic-silencing of pro-memory genes in effector T cells.

Active Maintenance of T Cell Memory in Acute and Chronic Viral Infection Depends on Continuous Expression of FOXO1

“…This might occur through de-differentiation from effector T cells after the resolution of an infection (Youngblood et al, 2017). This would be in line with the hypothesis of FOXO1 preventing the deposition of the H3K27me3 at that stage on certain pro-memory genes in CD8 + T cells and thus facilitating the expression and perhaps the maintenance of an extended memory signature (Gray et al, 2017). Further studies are necessary to precisely define the role(s) of FOXO1 in these early events.…”

“…This is in part extrinsically governed by a variety of FOXO1 post-translational modifications (Klotz et al, 2015), which in turn impact its cellular localization such that nuclear FOXO1 has been shown to strongly correlate with a memory fate (Lin et al, 2015; Verbist et al, 2016; Zhang et al, 2016). Furthermore, a recent study has proposed that FOXO1 potentially shields memory precursors from deposition of repression-associated histone 3 lysine 27 trimethyl (H3K27me3) chromatin modifications (Gray et al, 2017). Importantly, many experimental efforts to study the role of a specific transcription factor on T cell differentiation have been based on gene deletion, and such studies have provided insights into the transcriptional and molecular mechanisms leading to an effector or memory T cell.…”

Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity

“…Furthermore, single-cell gene expression analysis at the first division following infection reveals an early burst of transcriptional activity by daughter cells destined for terminal differentiation compared to memory-precursor cells at the same stage (Kakaradov et al 2017). This burst was followed by epigenetic silencing of genes associated with long-lived memory formation with deposition of H3K27me3 and a requirement of Ezh2 (Kakaradov et al 2017; Gray et al 2017). These recent studies further emphasize a role for epigenetic regulation at each stage of the CD8 + T cell response to infection and show that accessibility of specific regulatory regions by differentiation intermediates provide the basis for TF that are ubiquitously expressed to drive one cell fate over another.…”

Epigenetics of T cell aging

“…Epigenetic changes occur with T cell activation and differentiation . The acquisition of effector and memory T cell functions requires not only that genes involved in lineage commitment are turned on but also that genes maintaining stemness are repressed . Consequently, DNA methylation as well as DNA demethylation and histone modifications conferring gene activation as well as repression are required for T cells to differentiate .…”

“…Epigenetic patterns associated with differentiation have been mostly examined for naïve CD8+ T cells. These studies describe a loss of activation‐associated histone modifications, such as H3K4me3 and H3K9ac, and a gain in DNA methylation and H3K27me3 modifications at transcription factors that are associated with stemness or naivety, such as FOXO1 , KLF2 , LEF1 , and TCF7 . Not surprisingly, the opposite histone modification pattern was seen for effector cell‐associated transcription factors ( EOMES , TBX21 , and PRDM1 ) and functional effector genes ( GZMA , GZMB , PRF1 , IFNG ).…”