Generating long-lived CD8(+) T-cell memory: Insights from epigenetic programs

Abstract

T-cell-based immunological memory has the potential to provide the host with life-long protection against pathogen reexposure and thus offers tremendous promise for the design of vaccines targeting chronic infections or cancer. In order to exploit this potential in the design of new vaccines, it is necessary to understand how and when memory T cells acquire their poised effector potential, and moreover, how they maintain these properties during homeostatic proliferation. To gain insight into the persistent nature of memory T-cell functions, investigators have turned their attention to epigenetic mechanisms. Recent efforts have revealed that many of the properties acquired among memory T cells are coupled to stable changes in DNA methylation and histone modifications. Furthermore, it has recently been reported that the delineating features among memory T cells subsets are also linked to distinct epigenetic events, such as permissive and repressive histone modifications and DNA methylation programs, providing exciting new hypotheses regarding their cellular ancestry. Here, we review recent studies focused on epigenetic programs acquired during effector and memory T-cell differentiation and discuss how these data may shed new light on the developmental path for generating long-lived CD8(+) T-cell memory.

Keywords: CD8+ T cell; DNA methylation; Epigenetics; Histone modification; Memory; T-cell exhaustion.

Figure 1

Models for generation of effector and memory CD8 T cells. (A) Cartoon representation of antigen-specific T cell clonal expansion and contraction in response to an acute infection. Upon cognate antigen presentation, naïve antigen-specific CD8 T cell proliferate and increase their numbers 1×10⁵ fold as they differentiate into effector cells. Approximately 90–95% of these cells die during the contraction stage coinciding with a progressive change in phenotypic and functional properties of the surviving population of cells. CD8 T cells that survive the contraction stage of the immune response make up a heterogeneous pool of memory cells. The schematics (B) and (C) represent two distinct models of progressive memory T cell differentiation. According to the memory-to-effector differentiation model (B) the memory T cell subsets – stem-cell-like memory (T_scm), central-memory (T_cm) and effector-memory (T_em) arise during the early stages of activation of naïve T cells prior to effector stage of differentiation (Teff). The effector-to-memory differentiation model (C) suggests that early after activation of naïve T cells, memory precursor effector cells are generated which acquire effector functions but retain the potential to give rise to the memory subsets. In both models, strength and duration of exposure to antigen reduce the memory potential of the cells. Size of the arrow is reflective of the self-renewing capacity of the memory subsets.

Figure 2

Chromatin organization, accessibility and gene expression. (A) A cartoon overview of various levels of chromatin organization. To accommodate the ~2m long human genomic DNA into the nucleus of a cell, the DNA exists as highly condensed structures called chromosomes. Dense packaging of the DNA into the chromosome in mediated in part by nucleosomes, composed of a histone octamer with DNA wrapped around it. Modifications to histone tails (acetylation-orange bowtie, repressive-red triangle or permissive-green triangle methylation) alters nucleosomal density near the promoter of a gene and regulates the accessibility of the chromatin. Finally, cytosine methylation at CpGs within the promoter is thought to provide the cell-division transmissible component of epigenetic transcriptional regulation. (B) Transcriptionally repressed versus active genetic locus. A transcriptionally repressed gene is characterized by the presence of nucleosome, enrichment of repressive histone modifications (lack of acetylation, H3K27 methylation-red), and DNA methylation in the promoter sequence. These modifications maintain a compact chromatin state and restrict gene expression. A transcriptionally permissive gene is characterized by absence of nucleosomes near the transcriptional start site, enrichment of permissive histone modifications (acetylation and H3K4 methylation), and CpG demethylation within the promoter.

Figure 3

Maintenance versus plasticity of acquired transcriptional programs during memory T cell differentiation. (A) Unidirectional versus bidirectional Memory T cell differentiation models generate distinct hypotheses regarding the mechanism of transcriptional regulation. During unidirectional memory T cell differentiation, gene expression programs would arise during the antigen-dependent stage of the immune response. Such a model of on-off or off-on gene expression would predict only antigen-dependent epigenetic reprogramming events. Bidirectional memory T cell differentiation predicts effector gene expression programs are first acquired during the antigen-dependent stage of differentiation, but then further modified during the antigen-independent stage of the immune response. Such a model of off-on-off or on-off-on gene expression would predict antigen-independent epigenetic reprogramming events. (B) It remains to be determined whether the repressive epigenetic programs at homing receptor loci or the poised epigenetic programs at effector molecule loci acquired during memory CD8 T cell differentiation are maintained or erased in daughter cells during homeostatic proliferation or memory cell inter-conversion. These models also provide the opportunity to test whether stability and/or plasticity of the epigenetic programs facilitates the maintenance or pliability of transcriptional programs. Solid blue line indicates parental DNA and dashed blue line indicates the newly synthesized DNA strand. Repressive programs are shown as filled circles and red triangles, permissive programs are shown as open circles and green triangles.