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  • Review Article
  • Published:

Epigenetic control of T-helper-cell differentiation

Nature Reviews Immunology volume 9, pages 91–105 (2009)Cite this article

Key Points

  • Gene expression is regulated by transcription factors in concert with epigenetic modifications (such as DNA methylation, post-translational histone modifications, the position and compaction of nucleosomes and higher-order structural organization) at the gene regulatory elements where these factors can bind. Epigenetic modifications are heritable but plastic, thereby allowing cells to modify their gene expression patterns in response to changing contexts, as CD4+ T cells do in response to infection with different types of pathogen.

  • The pace of discovery in the field of epigenetics is accelerating through the application of new genomic approaches, which are yielding new insights on the gene regulatory mechanisms in T helper (TH) cells and other cell types. Compelling evidence indicates that epigenetic modifications at TH-cytokine and transcription factor gene loci work in concert with lineage-restricted transcription factors to govern cytokine expression and to stabilize lineage commitment.

  • During TH2-cell differentiation, GATA-binding protein 3 (GATA3) is necessary and apparently sufficient to induce TH2-type cytokine expression, as well as most, if not all, of the favourable epigenetic modifications to the TH2-cytokine locus and repressive modifications to the Ifng (interferon-γ) locus. Following these modifications, GATA3 contributes importantly to maintenance of the complete TH2-cell phenotype but is not absolutely essential for the maintenance of Il4 (interleukin-4) expression.

  • T-bet acts in concert with signal transducer and activator of transcription 4 (STAT4) during TH1-cell differentiation to induce IFNg expression and epigenetic remodelling of the Ifng locus, and to repress TH2-cytokine expression directly and through the inhibition of GATA3. The expression of T-bet does not seem to be essential for the maintenance of IFNg expression, but it is required to maintain certain other aspects of the TH1-cell phenotype.

  • The three-dimensional architecture of the TH2-cytokine and Ifng loci is modified by 'chromatin looping', which brings distal gene regulatory elements in proximity with genes they help to regulate in appropriate cell types.

  • Additional work is needed to determine how specific combinations of epigenetic modifications are established by networks of lineage-specifying transcription factors, whether, when and how they can later be removed or selectively modified, and their causal contribution to the stability or plasticity of TH-cell lineage specification.

Abstract

Naive CD4+ T cells give rise to T-helper-cell subsets with functions that are tailored to their respective roles in host defence. The specification of T-helper-cell subsets is controlled by networks of lineage-specifying transcription factors, which bind to regulatory elements in genes that encode cytokines and other transcription factors. The nuclear context in which these transcription factors act is affected by epigenetic processes, which allow programmes of gene expression to be inherited by progeny cells that at the same time retain the potential for change in response to altered environmental signals. In this Review, we describe these epigenetic processes and discuss how they collaborate to govern the fate and function of T helper cells.

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Figure 1: Cytokines and transcription factor networks regulate T-helper-cell differentiation.
Figure 2: Chromatin and chromatin modifications.
Figure 3: The T helper 2 cytokine locus in mouse T cells.
Figure 4: The Ifng locus in mouse naive, T helper 1 and T helper 2 cells and human CD4+ T cells.
Figure 5: The Il17a–Il17f locus in mouse naive, T helper 1, T helper 2 and T helper 17 cells.

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Acknowledgements

We apologize to the colleagues whose work was not discussed owing to space limitations. Work from the authors' laboratories was supported by the National Institutes of Health, USA (grant numbers R01-AI071272, R01-HD18184, N01-AI40069 and T32-AI07411).

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  1. Department of Immunology, University of Washington, Seattle, 98195, Washington, USA

    Christopher B. Wilson, Emily Rowell & Masayuki Sekimata

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Glossary

Epigenetic process

A process that affects gene expression without altering the sequences of bases in the DNA. Epigenetic changes are potentially heritable in the absence of the factors that initially induced them, and some propose that this term be restricted to those that are demonstrably heritable (although the broader definition is used here). In mammals, epigenetic processes that affect gene transcription include methylation of cytosines in CpG dinucleotides, post-translational histone modifications and changes to higher-order chromatin structure.

Chromatin

DNA and the proteins with which it is associated in the nucleus.

Notch

A transmembrane receptor that is involved in the pathway for direct cell–cell signalling through its association with a transmembrane ligand of the Delta or Jagged family on a neighbouring cell. The large intracellular domain of Notch is cleaved and travels to the nucleus to become a direct co-activator of the transcription factor recombination-signal-binding protein for immunoglobulin-κ J region (RBPJ).

Nucleosome

The basic structural subunit of chromatin, which consists of ∼156 base pairs of DNA wrapped around an octamer of histones.

Histone code

Post-translational modifications of histone tails that involve characteristic clusters of modifications, including acetylation, phosphorylation, ubiquitylation, methylation, sumoylation and ADP-ribosylation that combine to create an epigenetic mechanism for the regulation of gene expression.

Heterochromatin

Highly compacted chromatin that is transcriptionally inactive. Includes structural regions of the chromosome that lack genes (for example, centromeres; known as constitutive heterochromatin) as well as genes that are silenced in a given cell type (known as facultative heterochromatin).

Locus control region

A DNA sequence that is defined by its ability (in transgenic assays) to permit high-level, tissue-specific expression of a linked promoter at all integration sites.

Chromatin-remodelling complex

An enzymatic complex that carries out the remodelling of DNA–nucleosomal architecture and determines transcriptional activity. The SWI–SNF (switching-defective–sucrose non-fermenting) ATPases are an example of complexes that remodel chromatin.

DNaseI hypersensitive site

A region of chromatin (usually less than a few hundred base pairs) that is ∼100 times more sensitive to digestion by DNaseI than bulk chromatin and corresponds to regions in which nucleosomes are depleted. Regulatory elements, including enhancers, promoters and insulators, which are functional in the cells being assayed, typically map to these sites.

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Wilson, C., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 9, 91–105 (2009). https://doi.org/10.1038/nri2487

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