Abstract
During immune responses, T cells require tightly controlled expression of transcriptional programs to regulate the balance between beneficial and harmful immunity. These transcriptional programs are critical for the lineage specification of effector T cells, the production of effector cytokines and molecules, and the development and maintenance of memory T cells. An emerging theme is that post-translational modification of histones by methylation plays an important role in orchestrating the expression of transcriptional programs in T cells. In this article, we provide a broad overview of histone methylation signatures for effector molecules and transcription factors in T cells, and the functional importance of histone methyltransferases in regulating T-cell immune responses.
Papers of special note have been highlighted as: ▪ of interest
References
- 1 Wherry EJ, Ha SJ, Kaech SM et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity27,670–684 (2007).
- 2 Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol.26,677–704 (2008).
- 3 Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat. Rev. Cancer8,299–308 (2008).
- 4 Heslop HE. How I treat EBV lymphoproliferation. Blood114,4002–4008 (2009).
- 5 Teshima T, Maeda Y, Ozaki K. Regulatory T cells and IL-17-producing cells in graft-versus-host disease. Immunotherapy3,833–852 (2011).
- 6 Zhang N, Bevan MJ. CD8(+) T cells: foot soldiers of the immune system. Immunity35,161–168 (2011).
- 7 Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and therapy. Nat. Rev. Immunol.12,443–458 (2012).
- 8 Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol.12,749–761 (2012).
- 9 Restifo NP, Dudley ME, Rosenberg SA. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. Rev. Immunol.12,269–281 (2012).
- 10 Fearon DT. The expansion and maintenance of antigen-selected CD8(+) T cell clones. Adv. Immunol.96,103–139 (2007).
- 11 Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations (*). Annu. Rev. Immunol.28,445–489 (2010).
- 12 Amsen D, Antov A, Flavell RA. The different faces of Notch in T-helper-cell differentiation. Nat. Rev. Immunol.9,116–124 (2009).
- 13 Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. Immunity30,646–655 (2009).
- 14 Wilson CB, Rowell E, Sekimata M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol.9,91–105 (2009).
- 15 Strahl BD, Allis CD. The language of covalent histone modifications. Nature403,41–45 (2000).▪ Proposes the ‘histone code hypothesis’.
- 16 Jenuwein T, Allis CD. Translating the histone code. Science293,1074–1080 (2001).▪ Proposes the ‘histone code hypothesis’.
- 17 Ellis L, Atadja PW, Johnstone RW. Epigenetics in cancer: targeting chromatin modifications. Mol. Cancer Ther.8,1409–1420 (2009).
- 18 Badeaux AI, Shi Y. Emerging roles for chromatin as a signal integration and storage platform. Nat. Rev. Mol. Cell Biol.14,211–224 (2013).
- 19 Wu JI, Lessard J, Crabtree GR. Understanding the words of chromatin regulation. Cell136,200–206 (2009).
- 20 Kouzarides T. Chromatin modifications and their function. Cell128,693–705 (2007).
- 21 Kelly TK, De Carvalho DD, Jones PA. Epigenetic modifications as therapeutic targets. Nat. Biotechnol.28,1069–1078.
- 22 Kimura M et al. Regulation of Th 2 cell differentiation by mel-18, a mammalian polycomb group gene. Immunity15,275–287 (2001).
- 23 Yamashita M et al. Interleukin (IL)-4-independent maintenance of histone modification of the IL-4 gene loci in memory Th 2 cells. J. Biol. Chem.279,39454–39464 (2004).
- 24 Koyanagi M et al. EZH2 and histone 3 trimethyl lysine 27 associated with IL 4 and IL 13 gene silencing in Th 1 cells. J. Biol. Chem.280,31470–31477 (2005).
- 25 Yamashita M, Hirahara K, Shinnakasu R et al. Crucial role of MLL for the maintenance of memory T helper type 2 cell responses. Immunity24,611–622 (2006).▪ The first study demonstrating the role of histone methyltransferase MLL in memory T cells.
- 26 Chang S, Aune TM. Dynamic changes in histone-methylation ‘marks’ across the locus encoding interferon-gamma during the differentiation of T helper type 2 cells. Nat. Immunol.8,723–731 (2007).▪ The first study showing the dynamic changes in histone methylation marks in activated T cells during their differentiation into Th2 cells.
- 27 Jacob E, Hod-Dvorai R, Schif-Zuck S, Avni O. Unconventional association of the polycomb group proteins with cytokine genes in differentiated T helper cells. J. Biol. Chem.283,13471–13481 (2008).
- 28 Northrop JK, Wells AD, Shen H. Cutting edge: chromatin remodeling as a molecular basis for the enhanced functionality of memory CD8 T cells. J. Immunol.181,865–868 (2008).
- 29 Yamashita M, Kuwahara M, Suzuki A et al. Bmi 1 regulates memory CD4 T cell survival via repression of the Noxa gene. J. Exp. Med.205,1109–1120 (2008).
- 30 Juelich T, Sutcliffe EL, Denton A et al. Interplay between chromatin remodeling and epigenetic changes during lineage-specific commitment to granzyme B expression. J. Immunol.183,7063–7072 (2009).
- 31 Wei G, Wei L, Zhu J et al. Global mapping of H3K4me 3 and H3K27me 3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity30,155–167 (2009).▪ Presents genome-wide mapping of histone methylation signatures for genes associated with effector and memory T cells.
- 32 Roh TY, Cuddapah S, Cui K, Zhao K. The genomic landscape of histone modifications in human T cells. Proc. Natl Acad. Sci. USA103,15782–15787 (2006).▪ Presents genome-wide mapping of histone methylation signatures for genes associated with effector and memory T cells.
- 33 Araki Y, Wang Z, Zang C 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).▪ Presents genome-wide mapping of histone methylation signatures for genes associated with effector and memory T cells. Also characterizes the histone methylation marks in different subsets of CD8 T cells.
- 34 Murray K. The occurrence of epsilon-N-methyl lysine in histones. Biochemistry3,10–15 (1964).
- 35 Lehnertz B, Northrop JP, Antignano F et al. Activating and inhibitory functions for the histone lysine methyltransferase G9a in T helper cell differentiation and function. J. Exp. Med.207,915–922 (2010).▪ The first study demonstrating that the histone methyltransferase G9a has both activating and suppressing roles in effector differentiation.
- 36 Nakata Y, Brignier AC, Jin S et al. c-Myb Menin GATA-3, and MLL form a dynamic transcription complex that plays a pivotal role in human T helper type 2 cell development. Blood116,1280–1290 (2010).
- 37 Onodera A, Yamashita M, Endo Y et al. STAT6-mediated displacement of polycomb by trithorax complex establishes long-term maintenance of GATA3 expression in T helper type 2 cells. J. Exp. Med.207,2493–2506 (2010).
- 38 Kozuka T, Sugita M, Shetzline S, Gewirtz AM, Nakata Y. c-Myb and GATA-3 cooperatively regulate IL-13 expression via conserved GATA-3 response element and recruit mixed lineage leukemia (MLL) for histone modification of the IL-13 locus. J. Immunol.187,5974–5982 (2011).
- 39 Allan RS, Zueva E, Cammas F et al. An epigenetic silencing pathway controlling T helper 2 cell lineage commitment. Nature487,249–253 (2012).▪ Identifies the critical role of SUV39H1 in maintaining the stability of differentiated Th2 cells.
- 40 He S, Wang J, Kato K et al. Inhibition of histone methylation arrests ongoing graft-versus-host disease in mice by selectively inducing apoptosis of alloreactive effector T cells. Blood119,1274–1282 (2012).▪ First study reporting that inhibition of histone methylation can reduce alloreactive T-cell-mediated graft-versus-host disease.
- 41 Denton AE, Russ BE, Doherty PC, Rao S, Turner SJ. Differentiation-dependent functional and epigenetic landscapes for cytokine genes in virus-specific CD8+ T cells. Proc. Natl Acad. Sci. USA108,15306–15311 (2011).▪ Characterizes the histone methylation marks in different subsets of CD8 T cells.
- 42 Lu KT, Kanno Y, Cannons JL et al. Functional and epigenetic studies reveal multistep differentiation and plasticity of in vitro-generated and in vivo-derived follicular T helper cells. Immunity35,622–632 (2011).
- 43 Mukasa R Balasubramani A, Lee YK et al. Epigenetic instability of cytokine and transcription factor gene loci underlies plasticity of the T helper 17 cell lineage. Immunity32,616–627 (2010).
- 44 Boyle AP, Davis S, Shulha HP et al. High-resolution mapping and characterization of open chromatin across the genome. Cell132,311–322 (2008).
- 45 Cohen CJ, Crome SQ, MacDonald KG et al. Human Th 1 and Th 17 cells exhibit epigenetic stability at signature cytokine and transcription factor loci. J. Immunol.187,5615–5626 (2011).
- 46 O’Shea JJ, Paul WE. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science327,1098–1102.
- 47 Stockinger B, Veldhoen M. Differentiation and function of Th 17 T cells. Curr. Opin. Immunol.19,281–286 (2007).
- 48 Weaver CT, Hatton RD, Mangan PR, Harrington LE. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol.25,821–852 (2007).
- 49 Bernstein BE, Mikkelsen TS, Xie X et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell125,315–326 (2006).
- 50 Josefowicz SZ. Regulators of chromatin state and transcription in CD4 T-cell polarization. Immunology139,299–308.
- 51 Lee YK, Turner H, Maynard CL et al. Late developmental plasticity in the T helper 17 lineage. Immunity30,92–107 (2009).
- 52 Segal BM. Th 17 cells in autoimmune demyelinating disease. Semin. Immunopathol.32,71–77 (2010).
- 53 Zhang Y, Sandy AR, Wang J et al. Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. Blood117,299–308 (2011).
- 54 Carpenter AC, Grainger JR, Xiong Y et al. The transcription factors Thpok and LRF are necessary and partly redundant for T helper cell differentiation. Immunity37,622–633 (2012).
- 55 Zediak VP, Johnnidis JB, Wherry EJ, Berger SL. Cutting edge: persistently open chromatin at effector gene loci in resting memory CD8+ T cells independent of transcriptional status. J. Immunol.186,2705–2709 (2011).▪ Characterizes the histone methylation marks in different subsets of CD8 T cells.
- 56 Pearce EL, Mullen AC, Martins GA et al. Control of effector CD8+ T cell function by the transcription factor Eomesodermin. Science302,1041–1043 (2003).
- 57 Intlekofer AM, Takemoto N, Wherry EJ et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol.6,1236–1244 (2005).
- 58 Intlekofer AM, Takemoto N, Kao C et al. Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells. J. Exp. Med.204,2015–2021 (2007).
- 59 Joshi NS, Cui W, Chandele A et al. Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity27,281–295 (2007).
- 60 Paley MA, Kroy DC, Odorizzi PM et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science338,1220–1225 (2012).▪ Discovers that cooperation of different CD8 T-cell subsets is critical for effective immunity against chronic infection.
- 61 Martins G, Calame K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol.26,133–169 (2008).
- 62 Kallies A, Xin A, Belz GT, Nutt SL. Blimp-1 transcription factor is required for the differentiation of effector CD8(+) T cells and memory responses. Immunity31,283–295 (2009).
- 63 Rutishauser RL, Martins GA, Kalachikov S et al. Transcriptional repressor Blimp-1 promotes CD8(+) T cell terminal differentiation and represses the acquisition of central memory T cell properties. Immunity31,296–308 (2009).
- 64 Shin H, Blackburn SD, Intlekofer AM et al. A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity31,309–320 (2009).
- 65 Cannarile MA, Lind NA, Rivera R et al. Transcriptional regulator Id 2 mediates CD8+ T cell immunity. Nat. Immunol.7,1317–1325 (2006).
- 66 Kallies A. Distinct regulation of effector and memory T-cell differentiation. Immunol. Cell Biol.86,325–332 (2008).
- 67 Rea S, Eisenhaber F, O’Carroll D et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature406,593–599 (2000).
- 68 Greer EL, Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat. Rev. Genet.13,343–357 (2012).
- 69 Feng Q, Wang H, Ng HH et al. Methylation of H3-lysine 79 is mediated by a new family of HMTases without a SET domain. Curr. Biol.12,1052–1058 (2002).
- 70 Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res.21,381–395 (2011).
- 71 Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell128,735–745 (2007).
- 72 Margueron R, Reinberg D. The Polycomb complex PRC2 and its mark in life. Nature469,343–349 (2011).
- 73 Black JC, Van Rechem C, Whetstine JR. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell48,491–507 (2012).
- 74 Boyer LA, Plath K, Zeitlinger J et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature441,349–353 (2006).
- 75 Bracken AP, Kleine-Kohlbrecher D, Dietrich N et al. The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev.21,525–530 (2007).
- 76 Ringrose L, Paro R. Polycomb/Trithorax response elements and epigenetic memory of cell identity. Development134,223–232 (2007).
- 77 Bracken AP, Dietrich N, Pasini D, Hansen KH, Helin K. Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions. Genes Dev.20,1123–1136 (2006).
- 78 Ringrose L, Paro R. Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins. Annu. Rev. Genet.38,413–443 (2004).
- 79 Bannister AJ, Zegerman P, Partridge JF et al. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature410,120–124 (2001).
- 80 Lachner M, O’Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature410,116–120 (2001).
- 81 Tachibana M, Sugimoto K, Fukushima T, Shinkai Y. Set domain-containing protein G9a, is a novel lysine-preferring mammalian histone methyltransferase with hyperactivity and specific selectivity to lysines 9 and 27 of histone H3. J. Biol. Chem.276,25309–25317 (2001).
- 82 Tachibana M, Sugimoto K, Nozaki M et al. G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev.16,1779–1791 (2002).
- 83 Murphy E, Shibuya K, Hosken N et al. Reversibility of T helper 1 and 2 populations is lost after long-term stimulation. J. Exp. Med.183,901–913 (1996).
- 84 Grogan JL, Mohrs M, Harmon B, Lacy DA, Sedat JW, Locksley RM. Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity14,205–215 (2001).
- 85 Hagen EA, Stern H, Porter D et al. High rate of invasive fungal infections following nonmyeloablative allogeneic transplantation. Clin. Infect. Dis.36,9–15 (2003).
- 86 Muntean AG, Hess JL. The pathogenesis of mixed-lineage leukemia. Annu. Rev. Pathol.7,283–301 (2012).
- 87 Bantignies F, Cavalli G. Cellular memory and dynamic regulation of polycomb group proteins. Curr. Opin. Cell Biol.18,275–283 (2006).
- 88 Jacobs JJ, Kieboom K, Marino S, DePinho RA, van Lohuizen M. The oncogene and Polycomb-group gene BMI-1 regulates cell proliferation and senescence through the INK4a locus. Nature397,164–168 (1999).
- 89 Su IH, Dobenecker MW, Dickinson E et al. Polycomb group protein EZH 2 controls actin polymerization and cell signaling. Cell121,425–436 (2005).
- 90 Hod-Dvorai R, Jacob E, Boyko Y, Avni O. The binding activity of Mel-18 at the IL 17a promoter is regulated by the integrated signals of the TCR and polarizing cytokines. Eur. J. Immunol.41,2424–2435 (2011).
- 91 Jacob E, Hod-Dvorai R, Ben-Mordechai OL, Boyko Y, Avni O. Dual function of polycomb group proteins in differentiated murine T helper (CD4+) cells. J. Mol. Signal.6,5 (2011).
- 92 Kaech SM, Hemby S, Kersh E, Ahmed R. Molecular and functional profiling of memory CD8 T cell differentiation. Cell111,837–851 (2002).
- 93 Kaech SM, Wherry EJ Heterogeneity and cell-fate decisions in effector and memory CD8+ T cell differentiation during viral infection. Immunity27,393–405 (2007).
- 94 Kaech SM, Tan JT, Wherry EJ, Konieczny BT, Surh CD, Ahmed R. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol.4,1191–1198 (2003).
- 95 Wherry EJ, Teichgräber V, Becker TC et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol.4,225–234 (2003).
- 96 Kaech SM, Wherry EJ, Ahmed R. Effector and memory T-cell differentiation: implications for vaccine development. Nat. Rev. Immunol.2,251–262 (2002).
- 97 Wherry EJ, Ahmed R. Memory CD8 T-cell differentiation during viral infection. J. Virol.78,5535–5545 (2004).
- 98 Ahmed R, Bevan MJ, Reiner SL, Fearon DT. The precursors of memory: models and controversies. Nat. Rev. Immunol.9,662–668 (2009).
- 99 Fearon DT, Manders P, Wagner SD. Arrested differentiation, the self-renewing memory lymphocyte, and vaccination. Science293,248–250 (2001).
- 100 Sarkar S, Kalia V, Haining WN, Konieczny BT, Subramaniam S, Ahmed R. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J. Exp. Med.205,625–640 (2008).
- 101 Masopust D, Kaech SM, Wherry EJ, Ahmed R. The role of programming in memory T-cell development. Curr. Opin. Immunol.16,217–225 (2004).
- 102 Lanzavecchia A, Sallusto F. Dynamics of T lymphocyte responses: intermediates, effectors, and memory cells. Science290,92–97 (2000).
- 103 Williams MA, Bevan MJ. Effector and memory CTL differentiation. Annu. Rev. Immunol.25,171–192 (2007).
- 104 Kato K, Cui S, Kuick R 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).
- 105 Suzuki A, Iwamura C, Shinoda K et al. Polycomb group gene product Ring 1B regulates Th 2-driven airway inflammation through the inhibition of Bim-mediated apoptosis of effector Th 2 cells in the lung. J. Immunol.184,4510–4520 (2010).
- 106 Raaphorst FM, Otte AP, van Kemenade FJ et al. Distinct BMI-1 and EZH2 expression patterns in thymocytes and mature T cells suggest a role for polycomb genes in human T cell differentiation. J. Immunol.166,5925–5934 (2001).
- 107 van Kemenade FJ, Raaphorst FM, Blokzijl T et al. Coexpression of BMI-1 and EZH2 polycomb-group proteins is associated with cycling cells and degree of malignancy in B-cell non-Hodgkin lymphoma. Blood97,3896–3901 (2001).
- 108 Simon JA, Lange CA. Roles of the EZH2 histone methyltransferase in cancer epigenetics. Mutat. Res.647,21–29 (2008).
- 109 Liu J, Chen J, Song S et al. BMI 1 regulates mitochondrial function and the DNA damage response pathway. Nature459,387–392 (2009).
- 110 Viré E, Brenner C, Deplus R et al. The polycomb group protein EZH2 directly controls DNA methylation. Nature439,871–874 (2006).
- 111 Simon C, Chagraoui J, Krosl J et al. A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev.26,651–656 (2012).
- 112 Deaton AM, Bird A. CpG islands and the regulation of transcription. Genes Dev.25,1010–1022.
- 113 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.
- 114 Youngblood B, Hale JS, Ahmed R. T-cell memory differentiation: insights from transcriptional signatures and epigenetics. Immunology139,277–284.
- 115 Lewis MD, Miller SA, Miazgowicz MM, Beima KM, Weinmann AS. T-bet’s ability to regulate individual target genes requires the conserved T-box domain to recruit histone methyltransferase activity and a separate family member-specific transactivation domain. Mol. Cell Biol.27,8510–8521 (2007).
- 116 Miller SA, Huang AC, Miazgowicz MM, Brassil MM, Weinmann AS. Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression. Genes Dev.22,2980–2993 (2008).
- 117 Kaplan MH, Sun YL, Hoey T, Grusby MJ. Impaired IL-12 responses and enhanced development of Th 2 cells in Stat 4-deficient mice. Nature382,174–177 (1996).
- 118 Oestreich KJ, Weinmann AS. Transcriptional mechanisms that regulate T helper 1 cell differentiation. Curr. Opin. Immunol.24,191–195 (2012).
- 119 Zhu J, Min B, Hu-Li J et al. Conditional deletion of Gata 3 shows its essential function in T(h)1-T(h)2 responses. Nat. Immunol.5,1157–1165 (2004).
- 120 Ho IC, Pai SY. GATA-3 – not just for Th 2 cells anymore. Cell Mol. Immunol.4,15–29 (2007).
- 121 Ouyang W, Ranganath SH, Weindel K et al. Inhibition of Th 1 development mediated by GATA-3 through an IL-4-independent mechanism. Immunity9,745–755 (1998).
- 122 Usui T, Nishikomori R, Kitani A, Strober W. GATA-3 suppresses Th 1 development by downregulation of Stat 4 and not through effects on IL-12Rbeta 2 chain or T-bet. Immunity18,415–428 (2003).
- 123 Hwang ES, Szabo SJ, Schwartzberg PL, Glimcher LH. T helper cell fate specified by kinase-mediated interaction of T-bet with GATA-3. Science307,430–433 (2005).
- 124 Yagi R, Zhu J., Paul WE. An updated view on transcription factor GATA3-mediated regulation of Th 1 and Th 2 cell differentiation. Int. Immunol.23,415–420 (2011).
- 125 Chen GY, Osada H, Santamaria-Babi LF, Kannagi R. Interaction of GATA-3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th 1/Th 2 lymphocytes. Proc. Natl Acad. Sci. USA103,16894–16899 (2006).
- 126 Cuddapah S, Barski A, Zhao K. Epigenomics of T cell activation, differentiation, and memory. Curr. Opin. Immunol.22,341–347 (2010).
- 127 Grembecka J, He S, Shi A, Purohit T et al. Menin–MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat. Chem. Biol.8,277–284 (2012).
- 128 Else KJ, Finkelman FD, Maliszewski CR, Grencis RK. Cytokine-mediated regulation of chronic intestinal helminth infection. J. Exp. Med.179,347–351 (1994).
- 129 Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet373,1550–1561 (2009).
- 130 McCabe MT, Ott HM, Ganji G et al. EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature492,108–112 (2012).
- 131 Knutson SK, Wigle TJ, Warholic NM et al. A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nat. Chem. Biol.8,890–896 (2012).
- 132 Qi W, Chan H, Teng L et al. Selective inhibition of Ezh 2 by a small molecule inhibitor blocks tumor cells proliferation. Proc. Natl Acad. Sci. USA109,21360–21365 (2012).
- 133 Buchholz VR, Flossdorf M, Hensel I et al. Disparate individual fates compose robust CD8+ T cell immunity. Science340(6132),630–635 (2013).
- 134 Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Alloreactive memory T cells are responsible for the persistence of graft-versus-host disease. J. Immunol.174,3051–3058 (2005).
- 135 Zhang Y, Joe G, Hexner E, Zhu J, Emerson SG. Host-reactive CD8+ memory stem cells in graft-versus-host disease. Nat. Med.11,1299–1305 (2005).
- 136 Gattinoni L, Klebanoff CA, Palmer DC 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).
- 137 Gattinoni L, Lugli E, Ji Y et al. A human memory T cell subset with stem cell-like properties. Nat. Med.17,1290–1297 (2011).
- 138 Gattinoni L, Zhong XS, Palmer DC et al. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nat. Med.15,808–813 (2009).
- 139 Wang L, Jin Q, Lee JE, Su IH, Ge K. Histone H3K27 methyltransferase Ezh 2 represses Wnt genes to facilitate adipogenesis. Proc. Natl Acad. Sci. USA107,7317–7322 (2010).
- 140 Min J, Zaslavsky A, Fedele G et al. An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nat. Med.16,286–294 (2010).