Review Article | Published:

Epigenetic control of CD8+ T cell differentiation

Nature Reviews Immunology volume 18, pages 340356 (2018) | Download Citation


Upon stimulation, small numbers of naive CD8+ T cells proliferate and differentiate into a variety of memory and effector cell types. CD8+ T cells can persist for years and kill tumour cells and virally infected cells. The functional and phenotypic changes that occur during CD8+ T cell differentiation are well characterized, but the epigenetic states that underlie these changes are incompletely understood. Here, we review the epigenetic processes that direct CD8+ T cell differentiation and function. We focus on epigenetic modification of DNA and associated histones at genes and their regulatory elements. We also describe structural changes in chromatin organization that affect gene expression. Finally, we examine the translational potential of epigenetic interventions to improve CD8+ T cell function in individuals with chronic infections and cancer.

Key points

  • According to the linear differentiation model, progressive changes to gene expression and the epigenetic landscape regulate the gradual acquisition of effector function and restriction of differentiation potential that occur during CD8+ T cell differentiation.

  • DNA methylation, histone modification and chromatin architecture are major epigenetic mechanisms that regulate CD8+ T cell differentiation and function, allowing for signal-driven establishment and heritable maintenance of transcriptional changes.

  • Epigenetic modifying proteins can act differentially within CD8+ T cell differentiation subsets to regulate gene expression, and altering the activities of these enzymes can have profound effects on T cell differentiation and function.

  • T cell exhaustion represents a state of arrested differentiation. Reversal of T cell exhaustion liberates effector function but may negatively impact the persistence of antigen-specific T cells.

  • Increasing our understanding of the epigenetics underlying CD8+ T cell differentiation may enable a greater understanding of T cell biology and its enormous therapeutic possibilities.

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A.N.H. and N.P.R. are supported by the Cancer Moonshot program for the Center for Cell-based Therapy at the Center for Cancer Research, NCI/NIH (ZIA BC010763). This work was also supported by the Milstein Family Foundation. R.R is supported by the Wellcome Trust and Royal Society (grant 105663/Z/14/Z), the Lister Institute, the UK Biotechnology and Biological Sciences Research Council (grant BB/N007794/1) and Cancer Research UK (grant C52623/A22597). The authors thank L. Gattinoni, D. Palmer, M. Sukumar, D. Gurusamy, C. Klebanoff, D. Clever, R. Eil, F. Grant, R. Nasrallah, D. Gyori, C. Imianowski, F. Sadiyah, K. Okkenhaug, M. Turner, W. Reik, R. Vizcardo, G. Butcher and S. Rosenberg for ideas and discussion.

Author information


  1. Center for Cell-Based Therapy, National Cancer Institute (NCI).

    • Amanda N. Henning
    •  & Nicholas P. Restifo
  2. Surgery Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA.

    • Amanda N. Henning
    •  & Nicholas P. Restifo
  3. Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Cambridge CB22 3AT, UK.

    • Rahul Roychoudhuri


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A.N.H. researched data for the article. A.N.H. and R.R. made substantial contributions to discussion of the content, wrote the article and reviewed and edited the manuscript before submission. N.P.R. contributed to discussion of the content and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Rahul Roychoudhuri or Nicholas P. Restifo.


Chromatin architecture

The 3D organization of chromatin within the nucleus, which contributes to DNA packaging and protection and is also instrumental for gene regulation via the formation of discrete chromatin interactions.

Terminal effector differentiation

The final stage of CD8+ T cell differentiation, which follows the acquisition of effector function, precedes apoptosis and is characterized by cells that have lost stem-like characteristics, including pluripotency, self-renewal and persistence.

CpG islands

(CGIs). DNA regions that are commonly found at gene promoters and consist of a higher than average density of CG dinucleotide bases. Hypermethylation of these regions is associated with transcriptional repression.

Bivalent chromatin

Chromatin containing both activating H3K4me3 and repressive H3K27me3 modifications; often found at genes that are thought to be poised for future transcriptional activation or repression.

Super enhancers

Large regulatory loci with numerous clustered enhancer elements and multiple transcription factor binding sites. Super enhancers have been associated with cell identity and disease-associated genes.

Checkpoint inhibitor therapy

Therapy targeting either inhibitory cell surface receptors on T cells or their ligands expressed on cancer cells to circumvent tumour immunosuppression and boost antitumour immunity.

Adoptive cell therapy

(ACT). The administration of naturally occurring or genetically engineered tumour-reactive T cells to patients for cancer therapy.

Arrested effector model

An addendum to the developmental, or linear, differentiation model hypothesizing that CD8+ T cell exhaustion arises from T cells that become arrested before terminal effector differentiation. The stage at which cells arrest within canonical differentiation impacts their functionality as exhausted cells.

Cellular reprogramming

The manipulation of one cell type into another by altering the transcriptional, epigenetic and functional characteristics of the cell in a way that does not occur physiologically.

Pluripotent reprogramming

A type of cellular reprogramming that involves the conversion of a mature somatic cell into a less-differentiated, pluripotent cell type, referred to as an induced pluripotent stem cell.

Direct reprogramming

A type of cellular reprogramming that involves the conversion of a mature, differentiated somatic cell type into another mature cell type without passing through an intermediate induced pluripotent stem cell state.

Pioneer factors

Transcription factors that have the capacity to bind both open and closed chromatin. These proteins contribute to gene regulation by recruiting additional transcription factors and epigenetic modifying proteins and are critically important during cellular reprogramming.


Having characteristics associated with stem cells, specifically, the ability to self-renew and give rise to more differentiated progeny.

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