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

Nature Reviews Immunology volume 12, pages 306–315 (2012)Cite this article

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Key Points

  • Memory T cells, which are derived from naive T cells and carry the 'memory' of a previous exposure to an antigen, are long lived, have enhanced functional capacity compared with naive T cells and serve as the cellular basis of immunological memory.

  • Memory T cells are heterogeneous populations and can be divided into two main subsets: central memory T cells (which have stem cell-like properties and circulate in lymphoid organs) and effector memory T cells (which circulate in non-lymphoid tissues and perform rapid effector functions following activation).

  • Compared with naive T cells, memory T cells highly express a few hundred genes that have an array of functions and serve as the transcriptional basis for the unique function of memory T cells.

  • The highly expressed genes in memory T cells can be further divided into two main classes based on the pattern of their expression before and after antigen-mediated T cell activation. The first group includes genes that are highly expressed by resting memory T cells but not by resting naive T cells, whereas the second group includes genes that are expressed more highly by activated memory T cells than by activated naive T cells. Genes that are expressed at similar levels in resting naive and memory T cells but are more highly expressed by activated memory T cells than by activated naive T cells are called 'poised' genes.

  • Chromatin states (open or closed) are regulated by chemical modifications of DNA and histones; such modifications are considered to be epigenetic changes. The particular patterns of DNA methylation and histone modification are closely associated with the expression status of memory T cell highly expressed genes and may have a key role in the regulation of the differential gene expression and function of memory T cells.

  • A better understanding of the functions and epigenetic regulation of highly expressed genes in memory T cells will enable us to elucidate how memory T cell formation, maintenance and function, as well as the consequences of dysregulation of epigenetic changes, contribute to the altered function of the immune system in degenerative processes, such as autoimmunity and ageing.

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.

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Figure 1: Comparison of overall gene expression in naive and memory 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.
Figure 3: The chromatin basis for differential gene expression in memory T cells involves histone methylation.

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Acknowledgements

We thank R. Hodes, K. Zhao and the anonymous reviewers for critical reading of the manuscript and helpful suggestions. This research was supported by the Intramural Research Programs of the US National Institute on Aging, National Institutes of Health.

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  1. Laboratory of Molecular Biology and Immunology, National Institute on Aging, National Institutes of Health, 251 Bayview Blvd, Suite 100, Baltimore, 21224, Maryland, USA

    Nan-ping Weng, Yasuto Araki & Kalpana Subedi

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FURTHER INFORMATION

Gene Expression Omnibus

Glossary

Epigenetic regulation

The modifications on DNA, histones and other targets that collectively determine a stable phenotype without altering the DNA sequence. Epigenetic changes can pass from the parental cells to their offspring and provide a molecular basis for cellular memory.

Chromatin

The combination of DNA, histones and other proteins that comprises eukaryotic chromosomes. The basic repeating unit of chromatin is the nucleosome, which consists of an octamer of histone proteins around which ∼ 146 base pairs of DNA is wound.

Central memory T cells

(TCM cells). Antigen-experienced T cells that lack immediate effector function but can mediate rapid recall responses. They also rapidly develop the phenotype and function of effector memory T cells after re-stimulation with antigen. TCM cells retain the migratory properties of naive T cells and therefore circulate through the secondary lymphoid organs.

Effector memory T cells

(TEM cells). Terminally differentiated T cells that lack lymph node-homing receptors but express receptors that enable them to home to inflamed tissues. TEM cells can exert immediate effector functions without the need for further differentiation.

Microarray

A tool for measuring gene transcription. Its use involves the hybridization of fluorescently labelled cDNA prepared from a cell or tissue of interest with thousands of known oligonucleotides or cDNAs dotted on glass slides or other surfaces. The known DNA ideally represents all of the expressed genes in the species.

Heterochromatin

High-density regions in the nucleus that are thought to contain compacted chromatin structures associated with silent genes.

Chromatin immunoprecipitation

A technique that uses antibodies specific for transcription factors or other DNA-binding proteins to precipitate associated DNA sequences from chromatin to study their functional relationship.

Reverse transcription PCR

A type of PCR in which RNA is converted into complementary DNA (cDNA), which is then amplified.

ChIP–seq

A technique in which chromatin immunoprecipitation (ChIP) is followed by high-throughput sequencing to generate a genome-wide distribution map of protein–DNA interactions. This technique can be used to measure transcription factor binding and histone modifications.

Toll-like receptor

(TLR). A member of a family of receptors that are homologous to Drosophila melanogaster Toll. TLRs recognize conserved molecular patterns that are unique to microorganisms. The lipopolysaccharide component of bacterial cell walls is one such ligand. TLRs can also recognize mammalian components and contribute to autoimmunity.

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Weng, Np., Araki, Y. & Subedi, K. The molecular basis of the memory T cell response: differential gene expression and its epigenetic regulation. Nat Rev Immunol 12, 306–315 (2012). https://doi.org/10.1038/nri3173

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