The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation

Abstract

How the immune system remembers a previous encounter with a pathogen and responds more efficiently to a subsequent encounter has been one of the central enigmas for immunologists for over a century. The identification of pathogen-specific memory lymphocytes that arise after an infection provided a cellular basis for immunological memory. But the molecular mechanisms of immunological memory remain only partially understood. The emerging evidence suggests that epigenetic changes have a key role in controlling the distinct transcriptional profiles of memory lymphocytes and thus in shaping their function. In this Review, we summarize the recent progress that has been made in assessing the differential gene expression and chromatin modifications in memory CD4(+) and CD8(+) T cells, and we present our current understanding of the molecular basis of memory T cell function.

Figure 1. Comparison of overall gene expression in naive and memory T cells

The numbers in this figure are based on the analysis of nine published or deposited datasets from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database (dataset numbers GSE24759, GSE22880, GSE14422, GSE23663, GSE24151, GSE26928, GSE32596, GSE21360 and GSE13743). These datasets describe the differences in gene expression between naive and memory CD4⁺ and CD8⁺ T cells from humans and mice. Because different array analyses have different numbers of annotated genes, the genes that are expressed significantly more highly (expression difference fold > 2.0 and P< 0.05) in naive or memory T cells are presented as a percentage of the total number of genes analysed. The ranges reflect the lowest to the highest percentages in the nine datasets analysed here. In general, fewer genes are differentially expressed between naive and memory CD4⁺ T cells than between naive and memory CD8⁺ T cells.

Figure 2. Types of genes that are differentially expressed in memory T cells based on their expression kinetics before and after T cell activation

There are two main kinetic patterns of expression for genes that are expressed at higher levels in memory T cells than in naive T cells. First, there are genes that are highly expressed in resting memory T cells compared with resting naive T cells. These highly expressed genes in resting memory T cells include genes involved in migration, homeostasis and readiness for activation. Second, there are genes that are highly expressed only after the activation of memory T cells; these genes are termed poised genes. Such poised genes are tightly regulated when the T cell is in the resting state but are rapidly induced after T cell activation. It is apparent that the function of these poised genes is not desired in the resting state, and therefore they are minimally expressed. These two patterns of expression for genes that are highly expressed in memory T cells show that the expression of such genes is precisely controlled in a time- and space-dependent manner to fulfil the function of memory T cells.

Figure 3. The chromatin basis for differential gene expression in memory T cells involves histone methylation

There are four distinct modes of relationship between histone methylation and gene expression in memory T cells: active, poised, bivalent and repressed. In the active mode, the gene locus has an open chromatin state, which is indicated by high levels of trimethylation at histone H3 lysine 4 (H3K4me3; an activating modification), and there is active gene transcription (indicated by the presence of the transcription activator). In the poised mode, the gene locus has an open chromatin state, similar to that of the active mode, but there is no active gene transcription in resting memory T cells. However, following T cell activation, the transcription of genes in the poised mode can be rapidly initiated. Genes in the bivalent mode contain high levels of both H3K4me3 and the repressive modification H3K27me3 at their loci. Such a chromatin state can change in either direction (to an open or closed state) after T cell activation, and this is followed by the initiation or repression of gene transcription. Genes with a repressed chromatin state contain low levels of H3K4me3 but high levels of H3K27me3 at their loci, and thus their transcription is repressed. The unique chromatin landscape of memory T cells provides a structural basis for the differential gene expression and function of memory T cells. Pol II, RNA polymerase II.