Epigenetic control of CD8+ T cell differentiation (original) (raw)
Youngblood, B., Hale, J. S. & Ahmed, R. T-cell memory differentiation: insights from transcriptional signatures and epigenetics. Immunology139, 277–284 (2013). CASPubMedPubMed Central Google Scholar
Opferman, J. T., Ober, B. T. & Ashton-Rickardt, P. G. Linear differentiation of cytotoxic effectors into memory T lymphocytes. Science283, 1745–1748 (1999). CASPubMed Google Scholar
Akondy, R. S. et al. Origin and differentiation of human memory CD8 T cells after vaccination. Nature552, 362–367 (2017). CASPubMedPubMed Central Google Scholar
Youngblood, B. et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature552, 404–409 (2017). CASPubMedPubMed Central Google Scholar
Henning, A. N., Klebanoff, C. A. & Restifo, N. P. Silencing stemness in T cell differentiation. Science359, 163–164 (2018). CASPubMedPubMed Central Google Scholar
Restifo, N. P. & Gattinoni, L. Lineage relationship of effector and memory T cells. Curr. Opin. Immunol.25, 556–563 (2013). CASPubMed Google Scholar
Teixeiro, E. et al. Different T cell receptor signals determine CD8+ memory versus effector development. Science323, 502–505 (2009). CASPubMed Google Scholar
Wirth, T. C. et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity33, 128–140 (2010). CASPubMedPubMed Central Google Scholar
Kaech, S. M. & Cui, W. 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. CASPubMedPubMed Central Google Scholar
Roychoudhuri, R. et al. Transcriptional profiles reveal a stepwise developmental program of memory CD8+ T cell differentiation. Vaccine33, 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. CASPubMed Google Scholar
Willinger, T., Freeman, T., Hasegawa, H., McMichael, A. J. & Callan, M. F. Molecular signatures distinguish human central memory from effector memory CD8 T cell subsets. J. Immunol.175, 5895–5903 (2005). CASPubMed Google Scholar
Sarkar, S. et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med.205, 625–640 (2008). CASPubMedPubMed Central Google Scholar
Scott-Browne, J. P. et al. Dynamic changes in chromatin accessibility occur in CD8+ T cells responding to viral infection. Immunity45, 1327–1340 (2016). This study identifies unique chromatin accessibility patterns in CD8+ T cell subsets during acute and chronic viral infections. CASPubMedPubMed Central Google Scholar
He, B. et al. CD8+ T cells utilize highly dynamic enhancer repertoires and regulatory circuitry in response to infections. Immunity45, 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. CASPubMedPubMed Central Google Scholar
Gallimore, A. 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). CASPubMedPubMed Central Google Scholar
Zajac, A. J. et al. Viral immune evasion due to persistence of activated T cells without effector function. J. Exp. Med.188, 2205–2213 (1998). CASPubMedPubMed Central Google Scholar
Schietinger, A. & Greenberg, P. D. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol.35, 51–60 (2014). CASPubMed Google Scholar
Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol.36, 265–276 (2015). CASPubMedPubMed Central Google Scholar
Freeman, G. J. 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). CASPubMedPubMed Central Google Scholar
Hokey, D. A. et al. Activation drives PD-1 expression during vaccine-specific proliferation and following lentiviral infection in macaques. Eur. J. Immunol.38, 1435–1445 (2008). CASPubMedPubMed Central Google Scholar
Ahmadzadeh, M. et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood114, 1537–1544 (2009). CASPubMedPubMed Central Google Scholar
Fourcade, J. 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). CASPubMedPubMed Central Google Scholar
Matsuzaki, J. 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. USA107, 7875–7880 (2010). CASPubMedPubMed Central Google Scholar
Ball, M. P. et al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat. Biotechnol.27, 361–368 (2009). CASPubMedPubMed Central Google Scholar
Jones, P. A. 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. CASPubMed Google Scholar
Scharer, C. D., Barwick, B. G., Youngblood, B. A., Ahmed, R. & Boss, J. M. Global DNA methylation remodeling accompanies CD8 T cell effector function. J. Immunol.191, 3419–3429 (2013). CASPubMed Google Scholar
Rodriguez, R. M. et al. Epigenetic networks regulate the transcriptional program in memory and terminally differentiated CD8+ T cells. J. Immunol.198, 937–949 (2017). CASPubMed Google Scholar
Abdelsamed, H. A. et al. Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis. J. Exp. Med.214, 1593–1606 (2017). CASPubMedPubMed Central Google Scholar
Shin, M. S. 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). CASPubMed Google Scholar
Stadler, M. B. et al. DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature480, 490–495 (2011). CASPubMed Google Scholar
Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature454, 766–770 (2008). CASPubMedPubMed Central Google Scholar
Irizarry, R. A. 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). CASPubMedPubMed Central Google Scholar
Ji, H. et al. Comprehensive methylome map of lineage commitment from haematopoietic progenitors. Nature467, 338–342 (2010). CASPubMedPubMed Central Google Scholar
Branco, M. R., Ficz, G. & Reik, W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat. Rev. Genet.13, 7–13 (2011). PubMed Google Scholar
Araki, Y., Fann, M., Wersto, R. & Weng, N. P. 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). CASPubMed Google Scholar
Araki, Y. et al. Genome-wide analysis of histone methylation reveals chromatin state-based regulation of gene transcription and function of memory CD8+ T cells. Immunity30, 912–925 (2009). CASPubMedPubMed Central Google Scholar
Russ, B. E. et al. Distinct epigenetic signatures delineate transcriptional programs during virus-specific CD8+ T cell differentiation. Immunity41, 853–865 (2014). CASPubMedPubMed Central Google Scholar
Crompton, J. G. 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. CASPubMed Google Scholar
Juelich, T. et al. Interplay between chromatin remodeling and epigenetic changes during lineage-specific commitment to granzyme B expression. J. Immunol.183, 7063–7072 (2009). CASPubMed Google Scholar
Denton, A. E., Russ, B. E., Doherty, P. C., Rao, S. & Turner, S. J. Differentiation-dependent functional and epigenetic landscapes for cytokine genes in virus-specific CD8+ T cells. Proc. Natl Acad. Sci. USA108, 15306–15311 (2011). CASPubMedPubMed Central Google Scholar
Kuroda, S. 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. USA108, 14885–14889 (2011). CASPubMedPubMed Central Google Scholar
Shin, H. M. et al. Epigenetic modifications induced by Blimp-1 regulate CD8+ T cell memory progression during acute virus infection. Immunity39, 661–675 (2013). CASPubMed Google Scholar
Nguyen, M. L. 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). CASPubMed Google Scholar
Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature403, 41–45 (2000). This is a review on histone modifications and their general function. CASPubMed Google Scholar
Kimura, H. Histone modifications for human epigenome analysis. J. Hum. Genet.58, 439–445 (2013). CASPubMed Google Scholar
Geginat, J., Lanzavecchia, A. & Sallusto, F. Proliferation and differentiation potential of human CD8+ memory T-cell subsets in response to antigen or homeostatic cytokines. Blood101, 4260–4266 (2003). CASPubMed Google Scholar
Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell125, 315–326 (2006). CASPubMed Google Scholar
Pan, G. et al. Whole-genome analysis of histone H3 lysine 4 and lysine 27 methylation in human embryonic stem cells. Cell Stem Cell1, 299–312 (2007). CASPubMed Google Scholar
Zhao, X. D. et al. Whole-genome mapping of histone H3 Lys4 and 27 trimethylations reveals distinct genomic compartments in human embryonic stem cells. Cell Stem Cell1, 286–298 (2007). CASPubMed Google Scholar
Harker, N. et al. Pre-TCR signaling and CD8 gene bivalent chromatin resolution during thymocyte development. J. Immunol.186, 6368–6377 (2011). CASPubMed Google Scholar
Ing-Simmons, E. et al. Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin. Genome Res.25, 504–513 (2015). CASPubMedPubMed Central Google Scholar
Vahedi, G. et al. Super-enhancers delineate disease-associated regulatory nodes in T cells. Nature520, 558–562 (2015). CASPubMedPubMed Central Google Scholar
Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell153, 307–319 (2013). CASPubMedPubMed Central Google Scholar
Hnisz, D. et al. Super-enhancers in the control of cell identity and disease. Cell155, 934–947 (2013). CASPubMed Google Scholar
Kieffer-Kwon, K. R. et al. Interactome maps of mouse gene regulatory domains reveal basic principles of transcriptional regulation. Cell155, 1507–1520 (2013). CASPubMed Google Scholar
Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. 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. CASPubMedPubMed Central Google Scholar
Sarraf, S. A. & Stancheva, I. Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly. Mol. Cell15, 595–605 (2004). CASPubMed Google Scholar
Agarwal, N. et al. MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation. Nucleic Acids Res.35, 5402–5408 (2007). CASPubMedPubMed Central Google Scholar
Fujita, N. 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). CASPubMed Google Scholar
Kersh, E. N. Impaired memory CD8 T cell development in the absence of methyl-CpG-binding domain protein 2. J. Immunol.177, 3821–3826 (2006). CASPubMed Google Scholar
Musselman, C. A., Lalonde, M. E., Cote, J. & Kutateladze, T. G. Perceiving the epigenetic landscape through histone readers. Nat. Struct. Mol. Biol.19, 1218–1227 (2012). CASPubMedPubMed Central Google Scholar
Di Croce, L. & Helin, K. Transcriptional regulation by Polycomb group proteins. Nat. Struct. Mol. Biol.20, 1147–1155 (2013). CASPubMed Google Scholar
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y. & Greenleaf, W. J. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat. Methods10, 1213–1218 (2013). CASPubMedPubMed Central Google Scholar
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science354, 1160–1165 (2016). CASPubMedPubMed Central Google Scholar
Moskowitz, D. M. et al. Epigenomics of human CD8 T cell differentiation and aging. Sci. Immunol.2, eaag0192 (2017). PubMedPubMed Central Google Scholar
Heffner, M. & Fearon, D. T. Loss of T cell receptor-induced Bmi-1 in the KLRG1+ senescent CD8+ T lymphocyte. Proc. Natl Acad. Sci. USA104, 13414–13419 (2007). CASPubMedPubMed Central Google Scholar
Jacobs, J. J., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature397, 164–168 (1999). CASPubMed Google Scholar
Zhao, E. et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol.17, 95–103 (2016). CASPubMed Google Scholar
Kato, K. 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). CASPubMedPubMed Central Google Scholar
Gray, S. M., Amezquita, R. A., Guan, T., Kleinstein, S. H. & Kaech, S. M. Polycomb repressive complex 2-mediated chromatin repression guides effector CD8+ T cell terminal differentiation and loss of multipotency. Immunity46, 596–608 (2017). CASPubMedPubMed Central Google Scholar
He, S. et al. Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumour immunity. Nat. Commun.8, 2125 (2017). PubMedPubMed Central Google Scholar
Ladle, B. H. et al. De novo DNA methylation by DNA methyltransferase 3a controls early effector CD8+ T-cell fate decisions following activation. Proc. Natl Acad. Sci. USA113, 10631–10636 (2016). CASPubMedPubMed Central Google Scholar
Kakaradov, B. et al. Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat. Immunol.18, 422–432 (2017). CASPubMedPubMed Central Google Scholar
Pace, L. et al. The epigenetic control of stemness in CD8+ T cell fate commitment. Science359, 177–186 (2018). CASPubMed Google Scholar
Xing, S. et al. Tcf1 and Lef1 transcription factors establish CD8+ T cell identity through intrinsic HDAC activity. Nat. Immunol.17, 695–703 (2016). CASPubMedPubMed Central Google Scholar
Roychoudhuri, R. et al. BACH2 regulates CD8+ T cell differentiation by controlling access of AP-1 factors to enhancers. Nat. Immunol.17, 851–860 (2016). CASPubMedPubMed Central Google Scholar
Kagoya, Y. 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. PubMedPubMed Central Google Scholar
Lee, P. P. et al. A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. Immunity15, 763–774 (2001). CASPubMed Google Scholar
Pastor, W. A., Aravind, L. & Rao, A. TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat. Rev. Mol. Cell. Biol.14, 341–356 (2013). CASPubMedPubMed Central Google Scholar
Tsagaratou, A. et al. Dissecting the dynamic changes of 5-hydroxymethylcytosine in T-cell development and differentiation. Proc. Natl Acad. Sci. USA111, E3306–3315 (2014). CASPubMedPubMed Central Google Scholar
Carty, S. A. et al. The loss of TET2 promotes CD8+ T cell memory differentiation. J. Immunol.200, 82–91 (2018). CASPubMed Google Scholar
Lyko, F. & Brown, R. DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J. Natl Cancer Inst.97, 1498–1506 (2005). CASPubMed Google Scholar
Nora, E. P. et al. Spatial partitioning of the regulatory landscape of the X-inactivation centre. Nature485, 381–385 (2012). CASPubMedPubMed Central Google Scholar
Dixon, J. R. et al. Topological domains in mammalian genomes identified by analysis of chromatin interactions. Nature485, 376–380 (2012). CASPubMedPubMed Central Google Scholar
Fraser, J. et al. Hierarchical folding and reorganization of chromosomes are linked to transcriptional changes in cellular differentiation. Mol. Syst. Biol.11, 852 (2015). PubMedPubMed Central Google Scholar
Schmitt, A. D. et al. A compendium of chromatin contact maps reveals spatially active regions in the human genome. Cell Rep.17, 2042–2059 (2016). CASPubMedPubMed Central Google Scholar
Li, G. et al. Extensive promoter-centered chromatin interactions provide a topological basis for transcription regulation. Cell148, 84–98 (2012). CASPubMedPubMed Central Google Scholar
Phillips-Cremins, J. E. et al. Architectural protein subclasses shape 3D organization of genomes during lineage commitment. Cell153, 1281–1295 (2013). CASPubMedPubMed Central Google Scholar
Rao, S. S. et al. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell159, 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. CASPubMedPubMed Central Google Scholar
Javierre, B. M. et al. Lineage-specific genome architecture links enhancers and non-coding disease variants to target gene promoters. Cell167, 1369–1384.e19 (2016). CASPubMedPubMed Central Google Scholar
Lin, Y. C. 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). CASPubMedPubMed Central Google Scholar
Dekker, J., Rippe, K., Dekker, M. & Kleckner, N. Capturing chromosome conformation. Science295, 1306–1311 (2002). CASPubMed Google Scholar
Dekker, J., Marti-Renom, M. A. & Mirny, L. A. Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data. Nat. Rev. Genet.14, 390–403 (2013). CASPubMedPubMed Central Google Scholar
Shih, H. Y. et al. Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub. Proc. Natl Acad. Sci. USA109, E3493–E3502 (2012). CASPubMedPubMed Central Google Scholar
Tsytsykova, A. V. et al. Activation-dependent intrachromosomal interactions formed by the TNF gene promoter and two distal enhancers. Proc. Natl Acad. Sci. USA104, 16850–16855 (2007). CASPubMedPubMed Central Google Scholar
Spilianakis, C. G. & Flavell, R. A. Long-range intrachromosomal interactions in the T helper type 2 cytokine locus. Nat. Immunol.5, 1017–1027 (2004). CASPubMed Google Scholar
Ktistaki, E. et al. CD8 locus nuclear dynamics during thymocyte development. J. Immunol.184, 5686–5695 (2010). CASPubMed Google Scholar
Muto, A. et al. Nipbl and mediator cooperatively regulate gene expression to control limb development. PLOS Genet.10, e1004671 (2014). PubMedPubMed Central Google Scholar
Watson, L. A. et al. Dual effect of CTCF loss on neuroprogenitor differentiation and survival. J. Neurosci.34, 2860–2870 (2014). CASPubMedPubMed Central Google Scholar
Heath, H. et al. CTCF regulates cell cycle progression of alphabeta T cells in the thymus. EMBO J.27, 2839–2850 (2008). CASPubMedPubMed Central Google Scholar
Seitan, V. C. et al. Cohesin-based chromatin interactions enable regulated gene expression within preexisting architectural compartments. Genome Res.23, 2066–2077 (2013). CASPubMedPubMed Central Google Scholar
Ding, N. et al. Mediator links epigenetic silencing of neuronal gene expression with x-linked. mental retardation. Mol. Cell31, 347–359 (2008). CASPubMedPubMed Central Google Scholar
Tomaz, R. A. et al. Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation. Development144, 567–579 (2017). CASPubMedPubMed Central Google Scholar
Stephen, T. L. et al. SATB1 expression governs epigenetic repression of PD-1 in tumor-reactive T cells. Immunity46, 51–64 (2017). CASPubMedPubMed Central Google Scholar
Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science348, 62–68 (2015). This is a review of current ACT practices for cancer treatment and the challenges and future directions of the field. CASPubMedPubMed Central Google Scholar
Angelosanto, J. M., Blackburn, S. D., Crawford, A. & Wherry, E. J. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol.86, 8161–8170 (2012). CASPubMedPubMed Central Google Scholar
Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature545, 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. CASPubMedPubMed Central Google Scholar
Blackburn, S. D., Shin, H., Freeman, G. J. & Wherry, E. J. Selective expansion of a subset of exhausted CD8 T cells by αPD-L1 blockade. Proc. Natl Acad. Sci. USA105, 15016–15021 (2008). CASPubMedPubMed Central Google Scholar
Paley, M. A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science338, 1220–1225 (2012). CASPubMedPubMed Central Google Scholar
Wu, T. et al. The TCF1-Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol.1, eaai8593 (2016). PubMedPubMed Central Google Scholar
Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature537, 417–421 (2016). CASPubMedPubMed Central Google Scholar
He, R. et al. Follicular CXCR5- expressing CD8+ T cells curtail chronic viral infection. Nature537, 412–428 (2016). CASPubMed Google Scholar
Schietinger, A. et al. Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity45, 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. CASPubMedPubMed Central Google Scholar
Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature439, 682–687 (2006). CASPubMed Google Scholar
Duraiswamy, J., Freeman, G. J. & Coukos, G. 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). CASPubMed Google Scholar
Odorizzi, P. M., Pauken, K. E., Paley, M. A., Sharpe, A. & Wherry, E. J. 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. CASPubMedPubMed Central Google Scholar
Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell170, 142–157.e19 (2017). CASPubMedPubMed Central Google Scholar
Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity27, 670–684 (2007). CASPubMed Google Scholar
Doering, T. A. et al. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity37, 1130–1144 (2012). CASPubMedPubMed Central Google Scholar
Singer, M. et al. A distinct gene module for dysfunction uncoupled from activation in tumor-infiltrating T cells. Cell166, 1500–1511.e9 (2016). CASPubMedPubMed Central Google Scholar
Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA114, 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. CASPubMedPubMed Central Google Scholar
Simeonov, D. R. et al. Discovery of stimulation-responsive immune enhancers with CRISPR activation. Nature549, 111–115 (2017). CASPubMedPubMed Central Google Scholar
Gattinoni, L. 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). CASPubMedPubMed Central Google Scholar
Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res.17, 4550–4557 (2011). CASPubMedPubMed Central Google Scholar
Rufer, N., Dragowska, W., Thornbury, G., Roosnek, E. & Lansdorp, P. M. Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat. Biotechnol.16, 743–747 (1998). CASPubMed Google Scholar
Sommermeyer, D. et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia30, 492–500 (2016). CASPubMed Google Scholar
Klebanoff, C. A. et al. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy. J. Clin. Invest.126, 318–334 (2016). PubMed Google Scholar
Powell, D. J. Jr., Dudley, M. E., Robbins, P. F. & Rosenberg, S. A. Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy. Blood105, 241–250 (2005). CASPubMed Google Scholar
Gattinoni, L. et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med.15, 808–813 (2009). CASPubMedPubMed Central Google Scholar
Hinrichs, C. S. et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood111, 5326–5333 (2008). CASPubMedPubMed Central Google Scholar
Crompton, J. G. et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res.75, 296–305 (2015). CASPubMed Google Scholar
Tyrakis, P. A. et al. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature540, 236–241 (2016). This is a functional study demonstrating the impact that the metabolic intermediaryS-2HG can have on CD8+ T cell differentiation via epigenetic modulations. CASPubMedPubMed Central Google Scholar
Losman, J. A. & Kaelin, W. G. Jr. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev.27, 836–852 (2013). CASPubMedPubMed Central Google Scholar
O'Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol.16, 553–565 (2016). CASPubMedPubMed Central Google Scholar
Etchegaray, J. P. & Mostoslavsky, R. Interplay between metabolism and epigenetics: a nuclear adaptation to environmental changes. Mol. Cell62, 695–711 (2016). CASPubMedPubMed Central Google Scholar
Sukumar, M. et al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Invest.123, 4479–4488 (2013). CASPubMedPubMed Central Google Scholar
Crompton, J. G., Clever, D., Vizcardo, R., Rao, M. & Restifo, N. P. Reprogramming antitumor immunity. Trends Immunol.35, 178–185 (2014). CASPubMedPubMed Central Google Scholar
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell126, 663–676 (2006). CASPubMed Google Scholar
Themeli, M., Riviere, I. & Sadelain, M. New cell sources for T cell engineering and adoptive immunotherapy. Cell Stem Cell16, 357–366 (2015). CASPubMedPubMed Central Google Scholar
Soufi, A., Donahue, G. & Zaret, K. S. Facilitators and impediments of the pluripotency reprogramming factors' initial engagement with the genome. Cell151, 994–1004 (2012). CASPubMedPubMed Central Google Scholar
Zhang, H. et al. Intrachromosomal looping is required for activation of endogenous pluripotency genes during reprogramming. Cell Stem Cell13, 30–35 (2013). CASPubMed Google Scholar
Ang, Y. S. et al. Wdr5 mediates self-renewal and reprogramming via the embryonic stem cell core transcriptional network. Cell145, 183–197 (2011). CASPubMedPubMed Central Google Scholar
Chronis, C. et al. Cooperative binding of transcription factors orchestrates reprogramming. Cell168, 442–459.e20 (2017). CASPubMedPubMed Central Google Scholar
Mansour, A. A. et al. The H3K27 demethylase Utx regulates somatic and germ cell epigenetic reprogramming. Nature488, 409–413 (2012). CASPubMed Google Scholar
Wei, Z. et al. Klf4 organizes long-range chromosomal interactions with the Oct4 locus in reprogramming and pluripotency. Cell Stem Cell13, 36–47 (2013). CASPubMed Google Scholar
Yong, W. S., Hsu, F. M. & Chen, P. Y. Profiling genome-wide DNA methylation. Epigenetics Chromatin9, 26 (2016). PubMedPubMed Central Google Scholar
Crawford, G. E. et al. Genome-wide mapping of DNase hypersensitive sites using massively parallel signature sequencing (MPSS). Genome Res.16, 123–131 (2006). CASPubMedPubMed Central Google Scholar
Giresi, P. G., Kim, J., McDaniell, R. M., Iyer, V. R. & Lieb, J. D. FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin. Genome Res.17, 877–885 (2007). CASPubMedPubMed Central Google Scholar
Schoenfelder, S. et al. The pluripotent regulatory circuitry connecting promoters to their long-range interacting elements. Genome Res.25, 582–597 (2015). CASPubMedPubMed Central Google Scholar
Li, G. et al. Chromatin Interaction Analysis with Paired-End Tag (ChIA-PET) sequencing technology and application. BMC Genomics15 (Suppl. 12), S11 (2014). PubMedPubMed Central Google Scholar
Simons, B. D. & Clevers, H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell145, 851–862 (2011). CASPubMed Google Scholar
Lin, W. H. et al. Asymmetric PI3K signaling driving developmental and regenerative cell fate bifurcation. Cell Rep.13, 2203–2218 (2015). CASPubMedPubMed Central Google Scholar
Pollizzi, K. N. et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol.17, 704–711 (2016). CASPubMedPubMed Central Google Scholar
Verbist, K. C. et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature532, 389–393 (2016). CASPubMedPubMed Central Google Scholar
Nicholson, J. M. et al. Histone structures: targets for modifications by molecular assemblies. Ann. NY Acad. Sci.1030, 644–655 (2004). CASPubMed Google Scholar
Del Rizzo, P. A. & Trievel, R. C. Substrate and product specificities of SET domain methyltransferases. Epigenetics6, 1059–1067 (2011). CASPubMedPubMed Central Google Scholar
Fueyo, R., Garcia, M. A. & Martinez-Balbas, M. A. Jumonji family histone demethylases in neural development. Cell Tissue Res.359, 87–98 (2015). CASPubMed Google Scholar
Jeong, K. W. et al. Recognition of enhancer element-specific histone methylation by TIP60 in transcriptional activation. Nat. Struct. Mol. Biol.18, 1358–1365 (2011). CASPubMedPubMed Central Google Scholar
Li, H. et al. Molecular basis for site-specific read-out of histone H3K4me3 by the BPTF PHD finger of NURF. Nature442, 91–95 (2006). CASPubMedPubMed Central Google Scholar
Pradeepa, M. M., Sutherland, H. G., Ule, J., Grimes, G. R. & Bickmore, W. A. Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLOS Genet.8, e1002717 (2012). CASPubMedPubMed Central Google Scholar
Jin, Q. 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). CASPubMed Google Scholar
Sengupta, N. & Seto, E. Regulation of histone deacetylase activities. J. Cell. Biochem.93, 57–67 (2004). CASPubMed Google Scholar
Santos, L., Escande, C. & Denicola, A. Potential modulation of sirtuins by oxidative stress. Oxid Med. Cell Longev2016, 9831825 (2016). PubMed Google Scholar
Taniguchi, Y. The Bromodomain and Extra-Terminal Domain (BET) family: functional anatomy of BET paralogous proteins. Int. J. Mol. Sci.17, E1849 (2016). PubMed Google Scholar
Benevento, M., van de Molengraft, M., van Westen, R., van Bokhoven, H. & Kasri, N. N. 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). CASPubMed Google Scholar
Azzaz, A. M. et al. Human heterochromatin protein 1α promotes nucleosome associations that drive chromatin condensation. J. Biol. Chem.289, 6850–6861 (2014). CASPubMedPubMed Central Google Scholar
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature406, 593–599 (2000). CASPubMed Google Scholar
Rice, J. C. et al. Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol. Cell12, 1591–1598. CASPubMed Google Scholar