Review Article | Published:

Epigenetic control of CD8+ T cell differentiation

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

Abstract

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.

  • Subscribe to Nature Reviews Immunology for full access:

    $265

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    , & T-cell memory differentiation: insights from transcriptional signatures and epigenetics. Immunology 139, 277–284 (2013).

  2. 2.

    , & Linear differentiation of cytotoxic effectors into memory T lymphocytes. Science 283, 1745–1748 (1999).

  3. 3.

    et al. Origin and differentiation of human memory CD8 T cells after vaccination. Nature 552, 362–367 (2017).

  4. 4.

    et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552, 404–409 (2017).

  5. 5.

    , & Silencing stemness in T cell differentiation. Science 359, 163–164 (2018).

  6. 6.

    & Lineage relationship of effector and memory T cells. Curr. Opin. Immunol. 25, 556–563 (2013).

  7. 7.

    et al. Different T cell receptor signals determine CD8+ memory versus effector development. Science 323, 502–505 (2009).

  8. 8.

    et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity 33, 128–140 (2010).

  9. 9.

    & Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012). This is a review of the transcriptional pathways involved in CD8+ T cell differentiation and function during an acute immune response.

  10. 10.

    et al. Transcriptional profiles reveal a stepwise developmental program of memory CD8+ T cell differentiation. Vaccine 33, 914–923 (2015). This study analyses the transcriptional profiles of CD8+ T cell subsets during a vaccine-induced immune response, identifying progressive changes consistent with the linear model.

  11. 11.

    et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).

  12. 12.

    , , , & Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets. J. Immunol. 175, 5895–5903 (2005).

  13. 13.

    et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med. 205, 625–640 (2008).

  14. 14.

    et al. Dynamic changes in chromatin accessibility occur in CD8+ T cells responding to viral infection. Immunity 45, 1327–1340 (2016). This study identifies unique chromatin accessibility patterns in CD8+ T cell subsets during acute and chronic viral infections.

  15. 15.

    et al. CD8+ T cells utilize highly dynamic enhancer repertoires and regulatory circuitry in response to infections. Immunity 45, 1341–1354 (2016). In this study, the authors perform comprehensive mapping of enhancers and super enhancers in CD8+ T cell subsets, uncovering highly specific enhancer repertoires.

  16. 16.

    et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J. Exp. Med. 187, 1383–1393 (1998).

  17. 17.

    et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med. 188, 2205–2213 (1998).

  18. 18.

    & Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 35, 51–60 (2014).

  19. 19.

    & Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).

  20. 20.

    et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 192, 1027–1034 (2000).

  21. 21.

    et al. Activation drives PD-1 expression during vaccine-specific proliferation and following lentiviral infection in macaques. Eur. J. Immunol. 38, 1435–1445 (2008).

  22. 22.

    et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537–1544 (2009).

  23. 23.

    et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175–2186 (2010).

  24. 24.

    et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl Acad. Sci. USA 107, 7875–7880 (2010).

  25. 25.

    et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat. Biotechnol. 27, 361–368 (2009).

  26. 26.

    Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012). This is a review of the mechanisms and functions of DNA methylation in mammals.

  27. 27.

    , , , & Global DNA methylation remodeling accompanies CD8 T cell effector function. J. Immunol. 191, 3419–3429 (2013).

  28. 28.

    et al. Epigenetic networks regulate the transcriptional program in memory and terminally differentiated CD8+ T cells. J. Immunol. 198, 937–949 (2017).

  29. 29.

    et al. Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis. J. Exp. Med. 214, 1593–1606 (2017).

  30. 30.

    et al. DNA methylation regulates the differential expression of CX3CR1 on human IL-7Rαlow and IL-7Rαhigh effector memory CD8+ T cells with distinct migratory capacities to the fractalkine. J. Immunol. 195, 2861–2869 (2015).

  31. 31.

    et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature 480, 490–495 (2011).

  32. 32.

    et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).

  33. 33.

    et al. The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat. Genet. 41, 178–186 (2009).

  34. 34.

    et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature 467, 338–342 (2010).

  35. 35.

    , & Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat. Rev. Genet. 13, 7–13 (2011).

  36. 36.

    , , & Histone acetylation facilitates rapid and robust memory CD8 T cell response through differential expression of effector molecules (eomesodermin and its targets: perforin and granzyme B). J. Immunol. 180, 8102–8108 (2008).

  37. 37.

    et al. Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8+ T cells. Immunity 30, 912–925 (2009).

  38. 38.

    et al. Distinct epigenetic signatures delineate transcriptional programs during virus-specific CD8+ T cell differentiation. Immunity 41, 853–865 (2014).

  39. 39.

    et al. Lineage relationship of CD8+ T cell subsets is revealed by progressive changes in the epigenetic landscape. Cell. Mol. Immunol. 13, 502–513 (2016). This study identifies progressive, genome-wide changes in histone modifications in CD8+ T cell subsets, consistent with the linear model.

  40. 40.

    et al. Interplay between chromatin remodeling and epigenetic changes during lineage-specific commitment to granzyme B expression. J. Immunol. 183, 7063–7072 (2009).

  41. 41.

    , , , & Differentiation-dependent functional and epigenetic landscapes for cytokine genes in virus-specific CD8+ T cells. Proc. Natl Acad. Sci. USA 108, 15306–15311 (2011).

  42. 42.

    et al. Basic leucine zipper transcription factor, ATF-like (BATF) regulates epigenetically and energetically effector CD8 T-cell differentiation via Sirt1 expression. Proc. Natl Acad. Sci. USA 108, 14885–14889 (2011).

  43. 43.

    et al. Epigenetic modifications induced by Blimp-1 regulate CD8+ T cell memory progression during acute virus infection. Immunity 39, 661–675 (2013).

  44. 44.

    et al. Dynamic regulation of permissive histone modifications and GATA3 binding underpin acquisition of granzyme A expression by virus-specific CD8+ T cells. Eur. J. Immunol. 46, 307–318 (2016).

  45. 45.

    & The language of covalent histone modifications. Nature 403, 41–45 (2000). This is a review on histone modifications and their general function.

  46. 46.

    Histone modifications for human epigenome analysis. J. Hum. Genet. 58, 439–445 (2013).

  47. 47.

    , & Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood 101, 4260–4266 (2003).

  48. 48.

    et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125, 315–326 (2006).

  49. 49.

    et al. Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell Stem Cell 1, 299–312 (2007).

  50. 50.

    et al. Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell 1, 286–298 (2007).

  51. 51.

    et al. Pre-TCR signaling and CD8 gene bivalent chromatin resolution during thymocyte development. J. Immunol. 186, 6368–6377 (2011).

  52. 52.

    et al. Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin. Genome Res. 25, 504–513 (2015).

  53. 53.

    et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature 520, 558–562 (2015).

  54. 54.

    et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

  55. 55.

    et al. Super-enhancers in the control of cell identity and disease. Cell 155, 934–947 (2013).

  56. 56.

    et al. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell 155, 1507–1520 (2013).

  57. 57.

    , , & The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell. Biol. 16, 144–154 (2015). This is a review on the characteristics and function of enhancers and their role in regulating signal-driven transcriptional programmes.

  58. 58.

    & Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol. Cell 15, 595–605 (2004).

  59. 59.

    et al. MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation. Nucleic Acids Res. 35, 5402–5408 (2007).

  60. 60.

    et al. Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression. J. Biol. Chem. 278, 24132–24138 (2003).

  61. 61.

    Impaired memory CD8 T cell development in the absence of methyl-CpG-binding domain protein 2. J. Immunol. 177, 3821–3826 (2006).

  62. 62.

    , , & Perceiving the epigenetic landscape through histone readers. Nat. Struct. Mol. Biol. 19, 1218–1227 (2012).

  63. 63.

    & Transcriptional regulation by Polycomb group proteins. Nat. Struct. Mol. Biol. 20, 1147–1155 (2013).

  64. 64.

    et al. Regulation of alternative splicing by histone modifications. Science 327, 996–1000 (2010).

  65. 65.

    , , , & Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods 10, 1213–1218 (2013).

  66. 66.

    et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).

  67. 67.

    et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).

  68. 68.

    et al. Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol. 2, eaag0192 (2017).

  69. 69.

    & Loss of T cell receptor-induced Bmi-1 in the KLRG1+ senescent CD8+ T lymphocyte. Proc. Natl Acad. Sci. USA 104, 13414–13419 (2007).

  70. 70.

    , , , & The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999).

  71. 71.

    Principles of tumor suppression. Cell 116, 235–246 (2004).

  72. 72.

    et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol. 17, 95–103 (2016).

  73. 73.

    et al. Identification of stem cell transcriptional programs normally expressed in embryonic and neural stem cells in alloreactive CD8+ T cells mediating graft-versus-host disease. Biol. Blood Marrow Transplant. 16, 751–771 (2010).

  74. 74.

    , , , & Polycomb repressive complex 2-mediated chromatin repression guides effector CD8+ T cell terminal differentiation and loss of multipotency. Immunity 46, 596–608 (2017).

  75. 75.

    et al. Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumour immunity. Nat. Commun. 8, 2125 (2017).

  76. 76.

    et al. De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+ T-cell fate decisions following activation. Proc. Natl Acad. Sci. USA 113, 10631–10636 (2016).

  77. 77.

    et al. Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat. Immunol. 18, 422–432 (2017).

  78. 78.

    et al. The epigenetic control of stemness in CD8+ T cell fate commitment. Science 359, 177–186 (2018).

  79. 79.

    et al. Tcf1 and Lef1 transcription factors establish CD8+ T cell identity through intrinsic HDAC activity. Nat. Immunol. 17, 695–703 (2016).

  80. 80.

    et al. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. Nat. Immunol. 17, 851–860 (2016).

  81. 81.

    et al. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J. Clin. Invest. 126, 3479–3494 (2016). This is a functional study examining the effect of the bromodomain inhibitor JQ1 on T cell differentiation and antitumour activity and its underlying mechanism.

  82. 82.

    et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity 15, 763–774 (2001).

  83. 83.

    , & TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell. Biol. 14, 341–356 (2013).

  84. 84.

    et al. Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation. Proc. Natl Acad. Sci. USA 111, E3306–3315 (2014).

  85. 85.

    et al. The loss of TET2 promotes CD8+ T cell memory differentiation. J. Immunol. 200, 82–91 (2018).

  86. 86.

    & DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J. Natl Cancer Inst. 97, 1498–1506 (2005).

  87. 87.

    et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature 485, 381–385 (2012).

  88. 88.

    et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature 485, 376–380 (2012).

  89. 89.

    et al. Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation. Mol. Syst. Biol. 11, 852 (2015).

  90. 90.

    et al. A compendium of chromatin contact maps reveals spatially active regions in the human genome. Cell Rep. 17, 2042–2059 (2016).

  91. 91.

    et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell 148, 84–98 (2012).

  92. 92.

    et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell 153, 1281–1295 (2013).

  93. 93.

    et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell 159, 1665–1680 (2014). This study describes the application of Hi-C to multiple human and mouse cell lines, acquiring high-resolution data that enable the characterization of chromatin looping patterns in exquisite detail.

  94. 94.

    et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell 167, 1369–1384.e19 (2016).

  95. 95.

    et al. Global changes in the nuclear positioning of genes and intra- and interdomain genomic interactions that orchestrate B cell fate. Nat. Immunol. 13, 1196–1204 (2012).

  96. 96.

    , , & Capturing chromosome conformation. Science 295, 1306–1311 (2002).

  97. 97.

    , & Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat. Rev. Genet. 14, 390–403 (2013).

  98. 98.

    et al. Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub. Proc. Natl Acad. Sci. USA 109, E3493–E3502 (2012).

  99. 99.

    et al. Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers. Proc. Natl Acad. Sci. USA 104, 16850–16855 (2007).

  100. 100.

    & Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat. Immunol. 5, 1017–1027 (2004).

  101. 101.

    et al. CD8 locus nuclear dynamics during thymocyte development. J. Immunol. 184, 5686–5695 (2010).

  102. 102.

    et al. Nipbl and mediator cooperatively regulate gene expression to control limb development. PLOS Genet. 10, e1004671 (2014).

  103. 103.

    et al. Dual effect of CTCF loss on neuroprogenitor differentiation and survival. J. Neurosci. 34, 2860–2870 (2014).

  104. 104.

    et al. CTCF regulates cell cycle progression of alphabeta T cells in the thymus. EMBO J. 27, 2839–2850 (2008).

  105. 105.

    et al. Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments. Genome Res. 23, 2066–2077 (2013).

  106. 106.

    et al. Mediator links epigenetic silencing of neuronal gene expression with x-linked. mental retardation. Mol. Cell 31, 347–359 (2008).

  107. 107.

    et al. Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation. Development 144, 567–579 (2017).

  108. 108.

    et al. SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells. Immunity 46, 51–64 (2017).

  109. 109.

    & Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015). This is a review of current ACT practices for cancer treatment and the challenges and future directions of the field.

  110. 110.

    The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

  111. 111.

    , , & Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 86, 8161–8170 (2012).

  112. 112.

    et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017). This comprehensive analysis of chromatin accessibility during the early and later stages of T cell exhaustion demonstrates the therapeutic relevance of this type of analysis via pharmacological inhibition of a putative. exhaustion-associated transcription factor.

  113. 113.

    , , & Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. Proc. Natl Acad. Sci. USA 105, 15016–15021 (2008).

  114. 114.

    et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338, 1220–1225 (2012).

  115. 115.

    et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol. 1, eaai8593 (2016).

  116. 116.

    et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).

  117. 117.

    et al. Follicular CXCR5- expressing CD8+ T cells curtail chronic viral infection. Nature 537, 412–428 (2016).

  118. 118.

    et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 45, 389–401 (2016). This is an exhaustive study on the transcriptome of early-stage and late-stage exhausted T cells in a tumour-driven model demonstrating unique profiles at these stages and including comparisons with transcriptomes of viral-driven and self-tolerant models of T cell dysfunction.

  119. 119.

    et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439, 682–687 (2006).

  120. 120.

    , & Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res. 73, 6900–6912 (2013).

  121. 121.

    , , , & Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J. Exp. Med. 212, 1125–1137 (2015). This is a functional study showing that PD1 is not required for virally initiated T cell exhaustion but is needed to maintain the exhausted cell pool and prevent terminal differentiation.

  122. 122.

    et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157.e19 (2017).

  123. 123.

    et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

  124. 124.

    et al. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity 37, 1130–1144 (2012).

  125. 125.

    et al. A distinct gene module for dysfunction uncoupled from activation in tumor-infiltrating T cells. Cell 166, 1500–1511.e9 (2016).

  126. 126.

    et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017). This study demonstrates the innovative use of ATAC–seq to identify exhaustion-specific and activation-specific regulatory regions in a tumour-driven model of T cell exhaustion.

  127. 127.

    et al. Discovery of stimulation-responsive immune enhancers with CRISPR activation. Nature 549, 111–115 (2017).

  128. 128.

    et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J. Clin. Invest. 115, 1616–1626 (2005).

  129. 129.

    et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).

  130. 130.

    , , , & Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat. Biotechnol. 16, 743–747 (1998).

  131. 131.

    et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30, 492–500 (2016).

  132. 132.

    et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Invest. 126, 318–334 (2016).

  133. 133.

    , , & Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. Blood 105, 241–250 (2005).

  134. 134.

    et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med. 15, 808–813 (2009).

  135. 135.

    et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111, 5326–5333 (2008).

  136. 136.

    et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res. 75, 296–305 (2015).

  137. 137.

    et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540, 236–241 (2016). This is a functional study demonstrating the impact that the metabolic intermediary S-2HG can have on CD8+ T cell differentiation via epigenetic modulations.

  138. 138.

    & What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev. 27, 836–852 (2013).

  139. 139.

    , & A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553–565 (2016).

  140. 140.

    & Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol. Cell 62, 695–711 (2016).

  141. 141.

    et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest. 123, 4479–4488 (2013).

  142. 142.

    , , , & Reprogramming antitumor immunity. Trends Immunol. 35, 178–185 (2014).

  143. 143.

    & Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

  144. 144.

    , & New cell sources for T cell engineering and adoptive immunotherapy. Cell Stem Cell 16, 357–366 (2015).

  145. 145.

    , & Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell 151, 994–1004 (2012).

  146. 146.

    et al. Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming. Cell Stem Cell 13, 30–35 (2013).

  147. 147.

    et al. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell 145, 183–197 (2011).

  148. 148.

    et al. Cooperative binding of transcription factors orchestrates reprogramming. Cell 168, 442–459.e20 (2017).

  149. 149.

    et al. The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature 488, 409–413 (2012).

  150. 150.

    et al. Klf4 organizes long-range chromosomal interactions with the Oct4 locus in reprogramming and pluripotency. Cell Stem Cell 13, 36–47 (2013).

  151. 151.

    , & Profiling genome-wide DNA methylation. Epigenetics Chromatin 9, 26 (2016).

  152. 152.

    et al. Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS). Genome Res. 16, 123–131 (2006).

  153. 153.

    , , , & FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin. Genome Res. 17, 877–885 (2007).

  154. 154.

    et al. The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements. Genome Res. 25, 582–597 (2015).

  155. 155.

    et al. Chromatin Interaction Analysis with Paired-End Tag (ChIA-PET) sequencing technology and application. BMC Genomics 15 (Suppl. 12), S11 (2014).

  156. 156.

    & Strategies for homeostatic stem cell self-renewal in adult tissues. Cell 145, 851–862 (2011).

  157. 157.

    et al. Asymmetric PI3K signaling driving developmental and regenerative cell fate bifurcation. Cell Rep. 13, 2203–2218 (2015).

  158. 158.

    et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol. 17, 704–711 (2016).

  159. 159.

    et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389–393 (2016).

  160. 160.

    et al. Histone structures: targets for modifications by molecular assemblies. Ann. NY Acad. Sci. 1030, 644–655 (2004).

  161. 161.

    & Substrate and product specificities of SET domain methyltransferases. Epigenetics 6, 1059–1067 (2011).

  162. 162.

    , & Jumonji family histone demethylases in neural development. Cell Tissue Res. 359, 87–98 (2015).

  163. 163.

    et al. Recognition of enhancer element-specific histone methylation by TIP60 in transcriptional activation. Nat. Struct. Mol. Biol. 18, 1358–1365 (2011).

  164. 164.

    et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature 442, 91–95 (2006).

  165. 165.

    , , , & Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLOS Genet. 8, e1002717 (2012).

  166. 166.

    et al. Distinct roles of GCN5/PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac in nuclear receptor transactivation. EMBO J. 30, 249–262 (2011).

  167. 167.

    & Regulation of histone deacetylase activities. J. Cell. Biochem. 93, 57–67 (2004).

  168. 168.

    , & Potential modulation of sirtuins by oxidative stress. Oxid Med. Cell Longev 2016, 9831825 (2016).

  169. 169.

    The Bromodomain and Extra-Terminal Domain (BET) family: functional anatomy of BET paralogous proteins. Int. J. Mol. Sci. 17, E1849 (2016).

  170. 170.

    , , , & The role of chromatin repressive marks in cognition and disease: a focus on the repressive complex GLP/G9a. Neurobiol. Learn. Mem. 124, 88–96 (2015).

  171. 171.

    et al. Human heterochromatin protein 1α promotes nucleosome associations that drive chromatin condensation. J. Biol. Chem. 289, 6850–6861 (2014).

  172. 172.

    et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).

  173. 173.

    et al. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol. Cell 12, 1591–1598.

Download references

Acknowledgements

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

Affiliations

  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

Authors

  1. Search for Amanda N. Henning in:

  2. Search for Rahul Roychoudhuri in:

  3. Search for Nicholas P. Restifo in:

Contributions

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.

Glossary

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.

Stemness

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

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nri.2017.146

Rights and permissions

To obtain permission to re-use content from this article visit RightsLink.