T-cell memory differentiation: insights from transcriptional signatures and epigenetics

Abstract

A critical component of vaccine design is to generate and maintain antigen-specific memory lymphocytes of sufficient quantity and quality to give the host life-long protection against re-infection. Therefore, it is important to understand how memory T cells acquire the ability for self-renewal while retaining a potential for heightened recall of effector functions. During acute viral infection or following vaccination, antigen-specific T cells undergo extensive phenotypic and functional changes during differentiation to the effector and memory phases of the immune response. The changes in cell phenotype that accompany memory T-cell differentiation are predominantly mediated through acquired transcriptional regulatory mechanisms, in part achieved through epigenetic modifications of DNA and histones. Here we review our current understanding of epigenetic mechanisms regulating the off-on-off expression of CD8 and CD4 T-cell effector molecules at naive, effector and memory stages of differentiation, respectively, and how covalent modifications to the genome may serve as a mechanism to preserve 'poised' transcriptional states in homeostatically dividing memory cells. We discuss the potential of such mechanisms to control genes that undergo on-off-on patterns of expression including homing and pro-survival genes, and the implications on the development of effector-memory and central-memory T-cell differentiation. Lastly, we review recent studies demonstrating epigenetic modifications as a mechanism for the progressive loss of transcriptional adaptation in antigen-specific T cells that undergo sustained high levels of T-cell receptor signalling.

Figure 1

Adaptations in gene regulation during memory T-cell differentiation. (a) Naive antigen-specific CD8 T cells undergo clonal expansion upon presentation with the cognate antigen. The quantity of antigen-specific CD8 T cells at peak of clonal expansion is ∼ 1 × 10⁵ greater than the naive population. Approximately 90–95% of antigen-specific CD8 T cells die during the contraction stage of the immune response. A subset of effector cells progressively modify the transcriptional programme, acquiring homing and pro-survival properties before and into the contraction phase of the response. (b) Longitudinal gene expression profiling studies of total antigen-specific CD8 T cells during acute viral infection have revealed a group of genes that are expressed (green arrows) in naive cells, repressed (red circle) in effector cells, and re-expressed at different memory time points, i.e. on-off-on gene expression. Continuous treatment of mice with rapamycin at the effector stage of an acute immune response enhances the kinetics of gene re-expression in CD8 T cells. Persistence of antigen presentation during chronic viral infection retains the ‘off’ state for several genes in the category of on-off-on expression. (c) Off-on-off gene expression is coupled to the loss of repressive epigenetic transcriptional regulatory programmes at the effector stage of the immune response followed by reacquisition of repressive and poised epigenetic programmes. A hypothetical model for epigenetic regulation of on-off-on gene expression would involve reduction in chromatin accessibility and acquisition of repressive epigenetic programming at the effector stage of the immune response followed by permissive epigenetic programming and chromatin accessibility during the transition to central memory T cells. Acquisition of repressive epigenetic modifications are indicated by a filled circle marker on the purple line (DNA) at transcriptional regulatory regions. Chromatin accessibility is indicated by the absence of green histone octamers.