Transcriptional and Epigenetic Regulation of Effector and Memory CD8 T Cell Differentiation

Abstract

Immune protection and lasting memory are accomplished through the generation of phenotypically and functionally distinct CD8 T cell subsets. Understanding how these effector and memory T cells are formed is the first step in eventually manipulating the immune system for therapeutic benefit. In this review, we will summarize the current understanding of CD8 T cell differentiation upon acute infection, with a focus on the transcriptional and epigenetic regulation of cell fate decision and memory formation. Moreover, we will highlight the importance of high throughput sequencing approaches and single cell technologies in providing insight into genome-wide investigations and the heterogeneity of individual CD8 T cells.

Keywords: CD8 T cell; cell fate decision; epigenetic; memory differentiation; single cell sequencing; transcriptional.

Figure 1

Factors that regulate effector and memory cell fate decision. Following activation, antigen-specific naïve CD8 T cells proliferate and differentiate into a heterogeneous pool of effector T cells that consist of two major subsets: SLECs and MPECs. Majority of SLECs die by apoptosis during contraction phase, whereas MPECs survive and become long-lived memory cells. Numerous factors as depicted can contribute to this cell fate decision process, which include TCR signal strength, co-stimulatory/co-inhibitory molecules, cytokines, transcription factors, and epigenetic regulators.

Figure 2

Transcriptional and epigenetic profiling during naïve to effector to memory transition. (A) Gene clusters defined by the mRNA expression levels in naïve, SLECs and memory cells. Four major expression patterns emerged: genes that were up- or downregulated during the effector stage and persisted into the memory phase, and genes that were up- or downregulated during the effector phase and then reverted to the naive state. (B) CpG methylation levels of different genes in naïve, SLECs, MPECs and memory cells. Naïve/memory genes are similarly acquired CpG methylation in both SLECs and MPECs. MPECs, not SLECs, have the capacity to erase their newly acquired methylation programs and re-express naïve/memory genes as they develop into memory CD8 T cells. SLECs and MPECs both show demethylation of several effector-associated genes which remain demethylated in memory cells for a long period of time. (C) Histones posttranslational modification (PTM) and their functions that are essential for CD8 T cell differentiation. For example, the epigenetic bivalency for H3K27me3 and H3K4me3 represent an epigenetic state from which a gene can be rapidly activated or repressed depending on the differentiation pathways. (D) Differentially enriched motifs of transcription factors in naïve, effector and memory cells. Motif analysis identified the cell-subsets specific transcription factors binding sites in enhancer or promoter regions. Gray depicts highly enriched motifs.

Figure 3

Epigenetic regulation of cell fate decision during acute infection. There are two major transcriptional circuits in regulating CD8 T cell differentiation: one of them associated with effector function and another one is essential in naïve/memory cells controlling T cell quiescence and homeostasis. In naïve CD8 T cells, naïve/memory genes are open (epigenetically by TFs in red) and on (transcriptionally by TFs in blue), while the effector genes are closed and off. When naïve cells are activated, effector genes are turned on mainly by “pioneer TFs” (in red) in both SLECs and MPECs. These genetic regions remain open but poised as MPECs develop into memory cells. Transcriptional repression of naïve/memory genes in MPECs cells can be reversed in memory CD8 T cells through recruiting additional TFs (in blue) to restart gene expression. In contrast, SLECs lose the accessibility at these TF-bound cis-regulatory elements and therefore permanently turn off the naïve/memory gene expression. This leads to their loss of memory potential and long-term survival.

Figure 4

Two CD8 T cell differentiation models. (A) The asymmetric division model emphasizes the significance of asymmetric segregation of cytokine receptors and signals pathways as early as the first division in dictating the memory or effector potential of T cells. The proximal daughter cell (red) inherits molecules that make it more likely to become an effector cell, while the distal daughter (blue) inherits more memory-related molecules. The progressive differentiation model is a linear model in which the cumulative history of encounters with antigen and inflammation dictate the cell fate from a memory-like stage to terminally differentiated cells. (B) A method to depict “one cell, one fate” and “one cell, multiple fates” models. Single cell identity of a T cell can be profiled based on their transcriptome using scRNA-seq. TCRs are nature molecular tags to track T cells. Integration of TCR clonotypes to a gene expression profile on a single-cell level can monitor the dynamics of effect and memory CD8 T cell fate decision during infection.