Abstract
For the immune homeostasis, regulation of effector T cells is indispensable. This is performed by a distinct subclass of CD4+ T cell called “regulatory T cells” (Tregs). The Tregs express the canonical transcription factor called Forkhead box P3 (Foxp3) throughout their life span for their proper development and suppressive function, and the expression of Foxp3 is regarded as a reliable marker of Tregs. Tregs can be generated in the thymus, peripheral tissues, and even in vitro. Thus, Treg populations are divided into three groups. The first one is the Tregs generated in the thymus (thymic Treg, tTreg) and occupies the major fraction of the total Treg population in vivo. The second one is the minor fraction generated in periphery from naïve CD4+ T cells, when they meet cognate antigen under tolerogenic conditions (peripheral Treg, pTreg). Tregs can also be generated in vitro upon TCR activation in the presence of TGF-β (induced Treg, iTreg). Although all three Treg populations have suppressive activity in common, each population shows distinct genetic and epigenetic features. For instance, in Foxp3 gene there is a unique evolutionarily conserved intronic region with several CpG motifs, which is called CNS2 (conserved non-coding sequence 2). The CpG motifs in CNS2 are fully methylated in almost all Foxp3− T cells including CD4 single positive thymocytes (tTreg precursors), naïve CD4+ T cells (pTreg and iTreg precursors) and CD8+ T cells, and some Foxp3+ T cells such as iTregs. In contrast, they are fully demethylated in Tregs generated in vivo (tTregs and pTregs). This dichotomic pattern seen in CNS2 (de-)methylation has attracted researchers’ attention. In this chapter, we are going to discuss the underlying mechanisms of CNS2 demethylation in various types of Tregs and how vitamin C contributes to this process.
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Abbreviations
- 5hmC:
-
5-hydroxymethylcytosine
- 5mC:
-
5-methylcytosine
- CNS2:
-
Conserved non-coding sequence 2
- Dnmt:
-
DNA methyl transferase
- Foxp3:
-
Forkhead box P3
- IL:
-
Interleukin
- iTreg:
-
Induced Treg
- pTreg:
-
Peripheral Treg
- SVCT:
-
Sodium-dependent vitamin C transporter
- Tet:
-
Ten-eleven-translocation
- TGF-β:
-
Transforming growth factor-β
- Treg:
-
Regulatory T
- tTreg:
-
Thymic Treg
References
Allis CD, Jenuwein T (2016) The molecular hallmarks of epigenetic control. Nat Rev Genet 17:487–500
Blaschke K, Ebata KT, Karimi MM, Zepeda-Martinez JA, Goyal P, Mahapatra S, Tam A, Laird DJ, Hirst M, Rao A et al (2013) Vitamin C induces Tet-dependent DNA demethylation and a blastocyst-like state in ES cells. Nature 500:222–226
Cheng X (1995) Structure and function of DNA methyltransferases. Annu Rev Biophys Biomol Struct 24:293–318
d’Hennezel E, Ben-Shoshan M, Ochs HD, Torgerson TR, Russell LJ, Lejtenyi C, Noya FJ, Jabado N, Mazer B, Piccirillo CA (2009) FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome. N Engl J Med 361:1710–1713
Dickson KM, Gustafson CB, Young JI, Zuchner S, Wang G (2013) Ascorbate-induced generation of 5-hydroxymethylcytosine is unaffected by varying levels of iron and 2-oxoglutarate. Biochem Biophys Res Commun 439:522–527
Durant L, Watford WT, Ramos HL, Laurence A, Vahedi G, Wei L, Takahashi H, Sun HW, Kanno Y, Powrie F et al (2010) Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32:605–615
Feng Y, Arvey A, Chinen T, van der Veeken J, Gasteiger G, Rudensky AY (2014) Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158:749–763
Feuerer M, Hill JA, Kretschmer K, von Boehmer H, Mathis D, Benoist C (2010) Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc Natl Acad Sci USA 107:5919–5924
Floess S, Freyer J, Siewert C, Baron U, Olek S, Polansky J, Schlawe K, Chang HD, Bopp T, Schmitt E et al (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5:e38
Gorres KL, Raines RT (2010) Prolyl 4-hydroxylase. Crit Rev Biochem Mol Biol 45:106–124
Hori S (2011) Regulatory T cell plasticity: beyond the controversies. Trends Immunol 32:295–300
Huehn J, Beyer M (2015) Epigenetic and transcriptional control of Foxp3+ regulatory T cells. Semin Immunol 27:10–18
Huehn J, Polansky JK, Hamann A (2009) Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 9:83–89
Ichiyama K, Chen T, Wang X, Yan X, Kim BS, Tanaka S, Ndiaye-Lobry D, Deng Y, Zou Y, Zheng P et al (2015) The methylcytosine dioxygenase Tet2 promotes DNA demethylation and activation of cytokine gene expression in T cells. Immunity 42:613–626
Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y (2010) Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature 466:1129–1133
Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR (2006) The orphan nuclear receptor ROR gammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133
Jones PA, Liang G (2009) Rethinking how DNA methylation patterns are maintained. Nat Rev Genet 10:805–811
Kim HP, Leonard WJ (2007) CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 204:1543–1551
Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H (2014) Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med 20:62–68
Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 cells. Annu Rev Immunol 27:485–517
Kuiper C, Vissers MC (2014) Ascorbate as a co-factor for fe- and 2-oxoglutarate dependent dioxygenases: physiological activity in tumor growth and progression. Front Oncol 4:359
Li X, Liang Y, LeBlanc M, Benner C, Zheng Y (2014) Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158:734–748
Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234
May JM (2011) The SLC23 family of ascorbate transporters: ensuring that you get and keep your daily dose of vitamin C. Br J Pharmacol 164:1793–1801
Messerschmidt DM, Knowles BB, Solter D (2014) DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev 28:812–828
Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, Huehn J, Hori S (2012) Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36:262–275
Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N et al (2012) T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37:785–799
Pastor WA, Aravind L, Rao A (2013) TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol 14:341–356
Patel DD, Kuchroo VK (2015) Th17 cell pathway in human immunity: lessons from genetics and therapeutic interventions. Immunity 43:1040–1051
Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J (2008) DNA methylation controls Foxp3 gene expression. Eur J Immunol 38:1654–1663
Reik W, Dean W, Walter J (2001) Epigenetic reprogramming in mammalian development. Science 293:1089–1093
Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, Benoist C, Rudensky AY (2010) Stability of the regulatory T cell lineage in vivo. Science 329:1667–1671
Sakaguchi S, Powrie F (2007) Emerging challenges in regulatory T cell function and biology. Science 317:627–629
Sasidharan Nair V, Song MH, Oh KI (2016) Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner. J Immunol 196:2119–2131
Song MH, Nair VS, Oh KI (2016) Vitamin C enhances the expression of IL17 in a Jmjd2-dependent manner. BMB Rep 50:49–54
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L et al (2009) Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324:930–935
Toker A, Engelbert D, Garg G, Polansky JK, Floess S, Miyao T, Baron U, Duber S, Geffers R, Giehr P et al (2013) Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J Immunol 190:3180–3188
Yang BH, Floess S, Hagemann S, Deyneko IV, Groebe L, Pezoldt J, Sparwasser T, Lochner M, Huehn J (2015a) Development of a unique epigenetic signature during in vivo Th17 differentiation. Nucleic Acids Res 43:1537–1548
Yang R, Qu C, Zhou Y, Konkel JE, Shi S, Liu Y, Chen C, Liu S, Liu D, Chen Y et al (2015b) Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T cell differentiation and maintain immune homeostasis. Immunity 43:251–263
Young JI, Zuchner S, Wang G (2015) Regulation of the epigenome by vitamin C. Annu Rev Nutr 35:545–564
Yue X, Trifari S, Aijo T, Tsagaratou A, Pastor WA, Zepeda-Martinez JA, Lio CW, Li X, Huang Y, Vijayanand P et al (2016) Control of Foxp3 stability through modulation of TET activity. J Exp Med 213:377–397
Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463:808–812
Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M, Ashby M, Nakayama M, Rosenthal W, Bluestone JA (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10:1000–1007
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Nair, V.S., Oh, K.I. (2017). Vitamin C and DNA Demethylation in Regulatory T Cells. In: Patel, V., Preedy, V. (eds) Handbook of Nutrition, Diet, and Epigenetics. Springer, Cham. https://doi.org/10.1007/978-3-319-31143-2_30-1
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DOI: https://doi.org/10.1007/978-3-319-31143-2_30-1
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