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Regulatory T Cell Plasticity and Stability and Autoimmune Diseases

  • Runze Qiu
  • Liyu Zhou
  • Yuanjing Ma
  • Lingling Zhou
  • Tao Liang
  • Le Shi
  • Jun Long
  • Dongping Yuan
Article

Abstract

CD4+CD25+ regulatory T cells (Tregs) are a class of CD4+ T cells with immunosuppressive functions that play a critical role in maintaining immune homeostasis. However, in certain disease settings, Tregs demonstrate plastic differentiation, and the stability of these Tregs, which is characterized by the stable expression or protective epigenetic modifications of the transcription factor Foxp3, becomes abnormal. Plastic Tregs have some features of helper T (Th) cells, such as the secretion of Th-related cytokines and the expression of specific transcription factors in Th cells, but also still retain the expression of Foxp3, a feature of Tregs. Although such Th-like Tregs can secrete pro-inflammatory cytokines, they still possess a strong ability to inhibit specific Th cell responses. Therefore, the plastic differentiation of Tregs not only increases the complexity of the immune circumstances under pathological conditions, especially autoimmune diseases, but also shows an association with changes in the stability of Tregs. The plastic differentiation and stability change of Tregs play vital roles in the progression of diseases. This review focuses on the phenotypic characteristics, functions, and formation conditions of several plastic Tregs and also summarizes the changes of Treg stability and their effects on inhibitory function. Additionally, the effects of Treg plasticity and stability on disease prognosis for several autoimmune diseases were also investigated in order to better understand the relationship between Tregs and autoimmune diseases.

Keywords

Regulatory T cell Plasticity Stability Epigenetic modification Treg-specific demethylation region Autoimmune diseases 

Notes

Acknowledgments

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding Information

This work was supported by the National Natural Science Foundation of China (Grant No. 81573929, 81373232, 81673937, 81703815), Jiangsu Provincial Natural Science Foundation of China (Grant No. BK2012458), and Priority Academic Program Development of Jiangsu Higher Education Institutions.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Lee YH, Bae SC (2017) Association between functional CYP2D6 polymorphisms and susceptibility to autoimmune diseases: a meta-analysis. Immunol Investig 46(2):109–122CrossRefGoogle Scholar
  2. 2.
    Ortona E et al (2016) Sex-based differences in autoimmune diseases. Ann Ist Super Sanita 52(2):205–212PubMedGoogle Scholar
  3. 3.
    Marrack P, Kappler J, Kotzin BL (2001) Autoimmune disease: why and where it occurs. Nat Med 7(8):899–905PubMedCrossRefGoogle Scholar
  4. 4.
    Becker KG (2004) The common variants/multiple disease hypothesis of common complex genetic disorders. Med Hypotheses 62(2):309–317PubMedCrossRefGoogle Scholar
  5. 5.
    Tan Y et al (2016) CD24: from a hematopoietic differentiation antigen to a genetic risk factor for multiple autoimmune diseases. Clin Rev Allergy Immunol 50(1):70–83PubMedCrossRefGoogle Scholar
  6. 6.
    Gravano DM, Hoyer KK (2013) Promotion and prevention of autoimmune disease by CD8+ T cells. J Autoimmun 45:68–79PubMedCrossRefGoogle Scholar
  7. 7.
    Lee YH, Bae SC (2016) Association between interferon-gamma +874 T/a polymorphism and susceptibility to autoimmune diseases: a meta-analysis. Lupus 25(7):710–718PubMedCrossRefGoogle Scholar
  8. 8.
    Walecki M et al (2015) Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T-cells. Mol Biol Cell 26(15):2845–2857PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Hwangbo C et al (2016) Syntenin regulates TGF-beta1-induced Smad activation and the epithelial-to-mesenchymal transition by inhibiting caveolin-mediated TGF-beta type I receptor internalization. Oncogene 35(3):389–401PubMedCrossRefGoogle Scholar
  10. 10.
    Dardalhon V et al (2008) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(−) effector T cells. Nat Immunol 9(12):1347–1355PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Li F et al (2015) Insufficient secretion of IL-10 by Tregs compromised its control on over-activated CD4+ T effector cells in newly diagnosed adult immune thrombocytopenia patients. Immunol Res 61(3):269–280PubMedCrossRefGoogle Scholar
  12. 12.
    Subramanian M et al (2013) Treg-mediated suppression of atherosclerosis requires MYD88 signaling in DCs. J Clin Invest 123(1):179–188PubMedCrossRefGoogle Scholar
  13. 13.
    Bommireddy R et al (2003) TGF beta 1 inhibits Ca2+−calcineurin-mediated activation in thymocytes. J Immunol 170(7):3645–3652PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Li MO, Wan YY, Flavell RA (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26(5):579–591PubMedCrossRefGoogle Scholar
  15. 15.
    Zhang D et al (2015) Manipulating regulatory T cells: a promising strategy to treat autoimmunity. Immunotherapy 7(11):1201–1211PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Yang WY et al (2015) Pathological conditions re-shape physiological Tregs into pathological Tregs. Burns Trauma 3(1)Google Scholar
  17. 17.
    Jager A et al (2009) Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol 183(11):7169–7177PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Lohning M et al (2008) Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors. J Exp Med 205(1):53–61PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Bending D et al (2009) Highly purified Th17 cells from BDC2.5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. J Clin Invest 119(3):565–572PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Harbour SN et al (2015) Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. Proc Natl Acad Sci U S A 112(22):7061–7066PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Lee YK et al (2009) Late developmental plasticity in the T helper 17 lineage. Immunity 30(1):92–107PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Arterbery AS et al (2016) Production of proinflammatory cytokines by monocytes in liver-transplanted recipients with de novo autoimmune hepatitis is enhanced and induces TH1-like regulatory T cells. J Immunol 196(10):4040–4051PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Xu X et al (2017) IFN-gamma-producing Th1-like regulatory T cells may limit acute cellular renal allograft rejection: paradoxical post-transplantation effects of IFN-gamma. Immunobiology 222(2):280–290PubMedCrossRefGoogle Scholar
  24. 24.
    Zheng J et al (2011) Generation of human Th1-like regulatory CD4+ T cells by an intrinsic IFN-gamma- and T-bet-dependent pathway. Eur J Immunol 41(1):128–139PubMedCrossRefGoogle Scholar
  25. 25.
    Li Y et al (2016) USP21 prevents the generation of T-helper-1-like Treg cells. Nat Commun 7:13559PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Colbeck EJ et al (2015) Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors. Oncotarget 6(28):24649–24659PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Huang CH et al (2017) Oral administration with diosgenin enhances the induction of intestinal T helper 1-like regulatory T cells in a murine model of food allergy. Int Immunopharmacol 42:59–66PubMedCrossRefGoogle Scholar
  28. 28.
    Araya N et al (2014) HTLV-1 induces a Th1-like state in CD4+CCR4+ T cells. J Clin Invest 124(8):3431–3442PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Koch MA et al (2012) T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 37(3):501–510PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Lee JH et al (2015) E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1alpha to maintain regulatory T cell stability and suppressive capacity. Immunity 42(6):1062–1074PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Levine AG et al (2017) Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546(7658):421–425PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Venigalla RK et al (2012) Identification of a human Th1-like IFNgamma-secreting Treg subtype deriving from effector T cells. J Autoimmun 39(4):377–387PubMedCrossRefGoogle Scholar
  33. 33.
    Yamada A et al (2015) Impaired expansion of regulatory T cells in a neonatal thymectomy-induced autoimmune mouse model. Am J Pathol 185(11):2886–2897PubMedCrossRefGoogle Scholar
  34. 34.
    Hall BM et al (2015) Induction of antigen specific CD4(+)CD25(+)Foxp3(+)T regulatory cells from naive natural thymic derived T regulatory cells. Int Immunopharmacol 28(2):875–886PubMedCrossRefGoogle Scholar
  35. 35.
    Piconese S et al (2014) Human OX40 tunes the function of regulatory T cells in tumor and nontumor areas of hepatitis C virus-infected liver tissue. Hepatology 60(5):1494–1507PubMedCrossRefGoogle Scholar
  36. 36.
    Piconese S, Timperi E, Barnaba V (2014) Hardcore' OX40+ immunosuppressive regulatory T cells in hepatic cirrhosis and cancer. Oncoimmunology 3:e29257PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Dominguez-Villar M, Baecher-Allan CM, Hafler DA (2011) Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat Med 17(6):673–675PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    McClymont SA et al (2011) Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol 186(7):3918–3926PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Hall AO et al (2012) The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37(3):511–523PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Wang Y et al (2010) An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo. J Immunol 185(10):5983–5992PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Li L et al (2016) Block of both TGF-beta and IL-2 signaling impedes Neurophilin-1+ regulatory T cell and follicular regulatory T cell development. Cell Death Dis 7(10):e2439PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Daniel V, Trojan K, Opelz G (2016) Immunosuppressive drugs affect induction of IFNy+ Treg in vitro. Hum Immunol 77(1):146–152PubMedCrossRefGoogle Scholar
  43. 43.
    Noval RM et al (2015) Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42(3):512–523CrossRefGoogle Scholar
  44. 44.
    Hall BM et al (2013) Do natural T regulatory cells become activated to antigen specific T regulatory cells in transplantation and in autoimmunity? Front Immunol 4:208PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Massoud AH et al (2016) An asthma-associated IL4R variant exacerbates airway inflammation by promoting conversion of regulatory T cells to TH17-like cells. Nat Med 22(9):1013–1022PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Fujino M, Li XK (2013) Role of STAT3 in regulatory T lymphocyte plasticity during acute graft-vs.-host-disease. JAKSTAT 2(4):e24529PubMedPubMedCentralGoogle Scholar
  47. 47.
    Wang Y, Su MA, Wan YY (2011) An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35(3):337–348PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Afzali B et al (2010) Translational mini-review series on Th17 cells: induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 159(2):120–130PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Tarique M et al (2017) IL-12 and IL-23 modulate plasticity of FoxP3+ regulatory T cells in human Leprosy. Mol Immunol 83:72–81PubMedCrossRefGoogle Scholar
  50. 50.
    Coomes SM, Pelly VS, Wilson MS (2013) Plasticity within the alphabeta(+)CD4(+) T-cell lineage: when, how and what for? Open Biol 3(1):120157PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Lee W et al (2016) Transcription factor IRF8 controls Th1-like regulatory T-cell function. Cell Mol Immunol 13(6):785–794PubMedCrossRefGoogle Scholar
  52. 52.
    Nosko A et al (2017) T-bet enhances regulatory T cell fitness and directs control of Th1 responses in crescentic GN. J Am Soc Nephrol 28(1):185–196PubMedCrossRefGoogle Scholar
  53. 53.
    Verma ND et al (2014) Interleukin-12 (IL-12p70) promotes induction of highly potent Th1-Like CD4(+)CD25(+) T regulatory cells that inhibit allograft rejection in unmodified recipients. Front Immunol 5:190PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Jin HS et al (2013) Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Invest 123(11):4923–4934PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    MacDonald KG et al (2015) Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis. J Allergy Clin Immunol 135(4):946–955PubMedCrossRefGoogle Scholar
  56. 56.
    Moosbrugger-Martinz V et al (2016) Atopic dermatitis induces the expansion of thymus-derived regulatory T cells exhibiting a Th2-like phenotype in mice. J Cell Mol Med 20(5):930–938PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Zheng Y et al (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458(7236):351–356PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Sawant DV, Vignali DA (2014) Once a Treg, always a Treg? Immunol Rev 259(1):173–191PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Wohlfert EA et al (2011) GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest 121(11):4503–4515PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Malard F et al (2014) Increased Th17/Treg ratio in chronic liver GVHD. Bone Marrow Transplant 49(4):539–544PubMedCrossRefGoogle Scholar
  61. 61.
    Zhang C et al (2014) The alteration of Th1/Th2/Th17/Treg paradigm in patients with type 2 diabetes mellitus: Relationship with diabetic nephropathy. Hum Immunol 75(4):289–296PubMedCrossRefGoogle Scholar
  62. 62.
    Voo KS et al (2009) Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci U S A 106(12):4793–4798PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Kleinewietfeld M, Hafler DA (2013) The plasticity of human Treg and Th17 cells and its role in autoimmunity. Semin Immunol 25(4):305–312PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Cho SN et al (2014) Role of staphylococcal enterotoxin B on the differentiation of regulatory T cells in nasal polyposis. Am J Rhinol Allergy 28(1):e17–e24PubMedCrossRefGoogle Scholar
  65. 65.
    Chellappa S et al (2016) Regulatory T cells that co-express RORgammat and FOXP3 are pro-inflammatory and immunosuppressive and expand in human pancreatic cancer. Oncoimmunology 5(4):e1102828PubMedCrossRefGoogle Scholar
  66. 66.
    Lochner M et al (2008) In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+ T cells. J Exp Med 205(6):1381–1393PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Sefik E et al (2015) Individual intestinal symbionts induce a distinct population of RORgamma(+) regulatory T cells. Science 349(6251):993–997PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kitamura K, Farber JM, Kelsall BL (2010) CCR6 marks regulatory T cells as a colon-tropic, IL-10-producing phenotype. J Immunol 185(6):3295–3304PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Villares R et al (2009) CCR6 regulates EAE pathogenesis by controlling regulatory CD4+ T-cell recruitment to target tissues. Eur J Immunol 39(6):1671–1681PubMedCrossRefGoogle Scholar
  70. 70.
    Kluger MA et al (2014) Stat3 programs Th17-specific regulatory T cells to control GN. J Am Soc Nephrol 25(6):1291–1302PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Zhou L et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–240PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Beriou G et al (2009) IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113(18):4240–4249PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Krebs CF, Steinmetz OM (2016) CD4+ T cell fate in glomerulonephritis: a tale of Th1, Th17, and novel treg subtypes. Mediat Inflamm 2016:5393894CrossRefGoogle Scholar
  74. 74.
    Turner JE et al (2010) CCR6 recruits regulatory T cells and Th17 cells to the kidney in glomerulonephritis. J Am Soc Nephrol 21(6):974–985PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Kluger MA et al (2016) Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus. Kidney Int 89(1):158–166PubMedCrossRefGoogle Scholar
  76. 76.
    King C (2009) New insights into the differentiation and function of T follicular helper cells. Nat Rev Immunol 9(11):757–766PubMedCrossRefGoogle Scholar
  77. 77.
    Maceiras AR et al (2017) T follicular helper and T follicular regulatory cells have different TCR specificity. Nat Commun 8:15067PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Linterman MA et al (2011) Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 17(8):975–982PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Chung Y et al (2011) Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 17(8):983–988PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Chowdhury A et al (2015) Decreased T follicular regulatory cell/T follicular helper cell (TFH) in simian immunodeficiency virus-infected rhesus macaques may contribute to accumulation of TFH in chronic infection. J Immunol 195(7):3237–3247PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Zhou Q et al (2015) Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis. Ann Rheum Dis 74(6):1265–1274PubMedCrossRefGoogle Scholar
  82. 82.
    Nie J et al (2015) FOXP3(+) Treg cells and gender bias in autoimmune diseases. Front Immunol 6:493PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Chapman NM, Chi H (2014) mTOR signaling, Tregs and immune modulation. Immunotherapy 6(12):1295–1311PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Li X, Zheng Y (2015) Regulatory T cell identity: formation and maintenance. Trends Immunol 36(6):344–353PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Ellis SD et al (2014) Induced CD8+FoxP3+ Treg cells in rheumatoid arthritis are modulated by p38 phosphorylation and monocytes expressing membrane tumor necrosis factor alpha and CD86. Arthritis Rheumatol 66(10):2694–2705PubMedCrossRefGoogle Scholar
  86. 86.
    Chakraborty S et al (2017) Transcriptional regulation of FOXP3 requires integrated activation of both promoter and CNS regions in tumor-induced CD8+ Treg cells. Sci Rep 7(1):1628PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Park MK et al (2016) Amelioration of autoimmune arthritis by adoptive transfer of Foxp3-expressing regulatory B cells is associated with the Treg/Th17 cell balance. J Transl Med 14(1):191PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Melis D et al (2017) Cutting edge: increased autoimmunity risk in glycogen storage disease type 1b is associated with a reduced engagement of glycolysis in T cells and an impaired regulatory T cell function. J Immunol 198(10):3803–3808PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Prins JR et al (2015) Unstable Foxp3+ regulatory T cells and altered dendritic cells are associated with lipopolysaccharide-induced fetal loss in pregnant interleukin 10-deficient mice. Biol Reprod 93(4):95PubMedCrossRefGoogle Scholar
  90. 90.
    Rossetti M et al (2017) TCR repertoire sequencing identifies synovial Treg cell clonotypes in the bloodstream during active inflammation in human arthritis. Ann Rheum Dis 76(2):435–441PubMedCrossRefGoogle Scholar
  91. 91.
    Alvarez SE et al (2017) Methylation of FOXP3 TSDR underlies the impaired suppressive function of Tregs from long-term belatacept-treated kidney transplant patients. Front Immunol 8:219CrossRefGoogle Scholar
  92. 92.
    Paparo L et al (2016) Epigenetic features of FoxP3 in children with cow’s milk allergy. Clin Epigenetics 8:86PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wang L et al (2013) Mbd2 promotes foxp3 demethylation and T-regulatory-cell function. Mol Cell Biol 33(20):4106–4115PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Gu J et al (2017) Human CD39hi regulatory T cells present stronger stability and function under inflammatory conditions. Cell Mol Immunol 14(6):521–528PubMedCrossRefGoogle Scholar
  95. 95.
    Arroyo HR et al (2017) CD45RA distinguishes CD4+CD25+CD127−/low TSDR demethylated regulatory t cell subpopulations with differential stability and susceptibility to tacrolimus-mediated inhibition of suppression. Transplantation 101(2):302–309CrossRefGoogle Scholar
  96. 96.
    He X et al (2017) Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells. Sci Rep 7:43003PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Bailey-Bucktrout SL et al (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39(5):949–962PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Nair VS, Oh KI (2014) Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells. Biochem Biophys Res Commun 450(1):918–924PubMedCrossRefGoogle Scholar
  99. 99.
    Miyao T et al (2012) Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36(2):262–275PubMedCrossRefGoogle Scholar
  100. 100.
    Huss DJ et al (2015) In vivo maintenance of human regulatory T cells during CD25 blockade. J Immunol 194(1):84–92PubMedCrossRefGoogle Scholar
  101. 101.
    Kumar S et al (2013) CD4+CD25+ T regs with acetylated FoxP3 are associated with immune suppression in human leprosy. Mol Immunol 56(4):513–520PubMedCrossRefGoogle Scholar
  102. 102.
    Song X et al (2012) Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function. Cell Rep 1(6):665–675PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Wang L et al (2016) Ubiquitin-specific protease-7 inhibition impairs Tip60-dependent Foxp3+ T-regulatory cell function and promotes antitumor immunity. EBioMedicine 13:99–112PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Xiao Y et al (2014) Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Rep 7(5):1471–1480PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Du T et al (2013) Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers. Exp Mol Pathol 95(1):38–45PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Li J et al (2015) Mammalian sterile 20-like kinase 1 (Mst1) enhances the stability of forkhead box P3 (Foxp3) and the function of regulatory t cells by modulating Foxp3 acetylation. J Biol Chem 290(52):30762–30770PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Beier UH et al (2012) Histone deacetylases 6 and 9 and sirtuin-1 control Foxp3+ regulatory T cell function through shared and isoform-specific mechanisms. Sci Signal 5(229):ra45PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Du X et al (2014) Mst1/Mst2 regulate development and function of regulatory T cells through modulation of Foxo1/Foxo3 stability in autoimmune disease. J Immunol 192(4):1525–1535PubMedCrossRefGoogle Scholar
  109. 109.
    Kumar S et al (2017) Hepatic stellate cells increase the immunosuppressive function of natural Foxp3+ regulatory T cells via IDO-induced AhR activation. J Leukoc Biol 101(2):429–438PubMedCrossRefGoogle Scholar
  110. 110.
    Geng J et al (2017) The transcriptional coactivator TAZ regulates reciprocal differentiation of TH17 cells and Treg cells. Nat Immunol 18(7):800–812PubMedCrossRefGoogle Scholar
  111. 111.
    Li C et al (2014) MeCP2 enforces Foxp3 expression to promote regulatory T cells' resilience to inflammation. Proc Natl Acad Sci U S A 111(27):E2807–E2816PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Wu C et al (2014) Galectin-9-CD44 interaction enhances stability and function of adaptive regulatory T cells. Immunity 41(2):270–282PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Harb H et al (2015) Childhood allergic asthma is associated with increased IL-13 and FOXP3 histone acetylation. J Allergy Clin Immunol 136(1):200–202PubMedCrossRefGoogle Scholar
  114. 114.
    Deng G et al (2015) Pim-2 kinase influences regulatory T cell function and stability by mediating Foxp3 protein N-terminal phosphorylation. J Biol Chem 290(33):20211–20220PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Morawski PA et al (2013) Foxp3 protein stability is regulated by cyclin-dependent kinase 2. J Biol Chem 288(34):24494–24502PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Zhang Y et al (2016) Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells. Hum Vaccin Immunother 12(10):2512–2518PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Zhuo C et al (2014) Higher FOXP3-TSDR demethylation rates in adjacent normal tissues in patients with colon cancer were associated with worse survival. Mol Cancer 13:153PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Okada M et al (2014) Regulation of regulatory T cells: epigenetics and plasticity. Adv Immunol 124:249–273PubMedCrossRefGoogle Scholar
  119. 119.
    Huehn J, Beyer M (2015) Epigenetic and transcriptional control of Foxp3+ regulatory T cells. Semin Immunol 27(1):10–18PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Bending D et al (2014) Hypomethylation at the regulatory T cell-specific demethylated region in CD25hi T cells is decoupled from FOXP3 expression at the inflamed site in childhood arthritis. J Immunol 193(6):2699–2708PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Jiao J et al (2017) Proximity ligation assay to quantify Foxp3 acetylation in regulatory T cells. Methods Mol Biol 1510:287–293PubMedCrossRefGoogle Scholar
  122. 122.
    Liu Y et al (2014) Two histone/protein acetyltransferases, CBP and p300, are indispensable for Foxp3+ T-regulatory cell development and function. Mol Cell Biol 34(21):3993–4007PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Hori S (2014) Lineage stability and phenotypic plasticity of Foxp3(+) regulatory T cells. Immunol Rev 259(1):159–172PubMedCrossRefGoogle Scholar
  124. 124.
    Duarte JH et al (2009) Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol 39(4):948–955PubMedCrossRefGoogle Scholar
  125. 125.
    Bruce DL et al (2012) Protein phosphatase 5 modulates SMAD3 function in the transforming growth factor-beta pathway. Cell Signal 24(11):1999–2006PubMedCrossRefGoogle Scholar
  126. 126.
    Takimoto T et al (2010) Smad2 and Smad3 are redundantly essential for the TGF-beta-mediated regulation of regulatory T plasticity and Th1 development. J Immunol 185(2):842–855PubMedCrossRefGoogle Scholar
  127. 127.
    Verrecchia F et al (2001) Smad3/AP-1 interactions control transcriptional responses to TGF-beta in a promoter-specific manner. Oncogene 20(26):3332–3340PubMedCrossRefGoogle Scholar
  128. 128.
    Jiang R et al (2017) The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion. Nat Commun 8:15129PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Barsheshet Y et al (2017) CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A 114(23):6086–6091PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    van der Touw W et al (2013) Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol 190(12):5921–5925PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Rauch KS et al (2016) Id3 maintains Foxp3 expression in regulatory T cells by controlling a transcriptional network of E47, Spi-B, and SOCS3. Cell Rep 17(11):2827–2836PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Hsiao HW et al (2015) Deltex1 antagonizes HIF-1alpha and sustains the stability of regulatory T cells in vivo. Nat Commun 6:6353PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Takahashi R et al (2011) SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J Exp Med 208(10):2055–2067PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Zhang P et al (2013) PARP-1 controls immunosuppressive function of regulatory T cells by destabilizing Foxp3. PLoS One 8(8):e71590PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Singh K et al (2014) Superiority of rapamycin over tacrolimus in preserving nonhuman primate Treg half-life and phenotype after adoptive transfer. Am J Transplant 14(12):2691–2703PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Cheng LS et al (2017) HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection. Clin Sci (Lond) 131(5):381–394CrossRefGoogle Scholar
  137. 137.
    Zwang NA et al (2016) Selective sparing of human Tregs by pharmacologic inhibitors of the phosphatidylinositol 3-kinase and MEK pathways. Am J Transplant 16(9):2624–2638PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Han JM, Patterson SJ, Levings MK (2012) The role of the PI3K signaling pathway in CD4(+) T cell differentiation and function. Front Immunol 3:245PubMedPubMedCentralGoogle Scholar
  139. 139.
    Huynh A et al (2015) Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 16(2):188–196PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Shrestha S et al (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16(2):178–187PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Delgoffe GM et al (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501(7466):252–256PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Yadav M et al (2012) Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med 209(10):1713–1722 S1–19PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Weiss JM et al (2012) Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 209(10):1723–1742 S1PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Jeker LT et al (2013) DGCR8-mediated production of canonical microRNAs is critical for regulatory T cell function and stability. PLoS One 8(5):e66282PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Revilla-Nuin B et al (2017) Differential profile of activated regulatory T cell subsets and microRNAs in tolerant liver transplant recipients. Liver Transpl 23(7):933–945PubMedCrossRefGoogle Scholar
  146. 146.
    Zhou X et al (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10(9):1000–1007PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8(3):277–284PubMedCrossRefGoogle Scholar
  148. 148.
    Oldenhove G et al (2009) Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31(5):772–786PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Schaer DA et al (2013) GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol Res 1(5):320–331PubMedCrossRefGoogle Scholar
  150. 150.
    Overacre-Delgoffe AE et al (2017) Interferon-gamma drives Treg fragility to promote anti-tumor immunity. Cell 169(6):1130–1141.e11PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Sawant DV et al (2015) The transcriptional repressor Bcl6 controls the stability of regulatory T cells by intrinsic and extrinsic pathways. Immunology 145(1):11–23PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Layman A et al (2017) Ndfip1 restricts mTORC1 signalling and glycolysis in regulatory T cells to prevent autoinflammatory disease. Nat Commun 8:15677PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Belle L et al (2016) Blockade of interleukin-27 signaling reduces GVHD in mice by augmenting Treg reconstitution and stabilizing Foxp3 expression. Blood 128(16):2068–2082PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Knosp CA et al (2013) Regulation of Foxp3+ inducible regulatory T cell stability by SOCS2. J Immunol 190(7):3235–3245PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Butcher MJ et al (2016) Atherosclerosis-driven Treg plasticity results in formation of a dysfunctional subset of plastic IFNgamma+ Th1/Tregs. Circ Res 119(11):1190–1203PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Trojan K et al (2017) Helios expression and Foxp3 TSDR methylation of IFNy+ and IFNy- Treg from kidney transplant recipients with good long-term graft function. PLoS One 12(3):e0173773PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Yang BH et al (2016) Foxp3(+) T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol 9(2):444–457PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Trojan K et al (2016) IFNy+ and IFNy- Treg subsets with stable and unstable Foxp3 expression in kidney transplant recipients with good long-term graft function. Transpl ImmunolGoogle Scholar
  159. 159.
    Daniel V et al (2015) IFNgamma+ Treg in-vivo and in-vitro represent both activated nTreg and peripherally induced aTreg and remain phenotypically stable in-vitro after removal of the stimulus. BMC Immunol 16:45PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Alpdogan O, van den Brink MR (2012) Immune tolerance and transplantation. Semin Oncol 39(6):629–642PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Zeng H et al (2015) Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. Cell Mol Immunol 12(5):566–571PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    van Delft MA, Huitema LF, Tas SW (2015) The contribution of NF-kappaB signalling to immune regulation and tolerance. Eur J Clin Investig 45(5):529–539CrossRefGoogle Scholar
  163. 163.
    La Rocca C et al (2014) The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett 162(1 Pt A):41–48PubMedCrossRefGoogle Scholar
  164. 164.
    Herkel J (2015) Regulatory T cells in hepatic immune tolerance and autoimmune liver diseases. Dig Dis 33(Suppl 2):70–74PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Cortes JR et al (2014) Maintenance of immune tolerance by Foxp3+ regulatory T cells requires CD69 expression. J Autoimmun 55:51–62PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Izcue A, Coombes JL, Powrie F (2009) Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27:313–338PubMedCrossRefPubMedCentralGoogle Scholar
  167. 167.
    Wing K, Sakaguchi S (2010) Regulatory T cells exert checks and balances on self tolerance and autoimmunity. Nat Immunol 11(1):7–13PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Cvetanovich GL, Hafler DA (2010) Human regulatory T cells in autoimmune diseases. Curr Opin Immunol 22(6):753–760PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Komatsu N et al (2014) Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med 20(1):62–68PubMedCrossRefPubMedCentralGoogle Scholar
  170. 170.
    Schinnerling K et al (2017) The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis. Clin Exp Immunol 189(1):12–20PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Wang T et al (2015) Regulatory T cells in rheumatoid arthritis showed increased plasticity toward Th17 but retained suppressive function in peripheral blood. Ann Rheum Dis 74(6):1293–1301PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Xia M et al (2017) Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity. Nat Commun 8:15818PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Nie H et al (2013) Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med 19(3):322–328PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Rossetti M et al (2015) Ex vivo-expanded but not in vitro-induced human regulatory T cells are candidates for cell therapy in autoimmune diseases thanks to stable demethylation of the FOXP3 regulatory T cell-specific demethylated region. J Immunol 194(1):113–124PubMedCrossRefPubMedCentralGoogle Scholar
  175. 175.
    Muto G et al (2013) TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity. PLoS One 8(9):e74639PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Jamshidian A et al (2013) Biased Treg/Th17 balance away from regulatory toward inflammatory phenotype in relapsed multiple sclerosis and its correlation with severity of symptoms. J Neuroimmunol 262(1–2):106–112PubMedCrossRefGoogle Scholar
  177. 177.
    AP J et al (2017) Altered regulatory T-cell fractions and Helios expression in clinically isolated syndrome:clues to the development of multiple sclerosis. Clin Transl Immunol 6(5):e143CrossRefGoogle Scholar
  178. 178.
    Nyirenda MH et al (2015) TLR2 stimulation regulates the balance between regulatory T cell and Th17 function: a novel mechanism of reduced regulatory T cell function in multiple sclerosis. J Immunol 194(12):5761–5774PubMedCrossRefGoogle Scholar
  179. 179.
    Rakebrandt N, Littringer K, Joller N (2016) Regulatory T cells: balancing protection versus pathology. Swiss Med Wkly 146:w14343PubMedGoogle Scholar
  180. 180.
    Kitz A et al (2016) AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Rep 17(8):1169–1183PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    O'Connor RA et al (2010) Myelin-reactive, TGF-beta-induced regulatory T cells can be programmed to develop Th1-like effector function but remain less proinflammatory than myelin-reactive Th1 effectors and can suppress pathogenic T cell clonal expansion in vivo. J Immunol 185(12):7235–7243PubMedCrossRefGoogle Scholar
  182. 182.
    Cerosaletti K et al (2013) Multiple autoimmune-associated variants confer decreased IL-2R signaling in CD4+ CD25(hi) T cells of type 1 diabetic and multiple sclerosis patients. PLoS One 8(12):e83811PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Fletcher JM et al (2009) CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 183(11):7602–7610PubMedCrossRefGoogle Scholar
  184. 184.
    Muls NG et al (2015) Regulation of Treg-associated CD39 in multiple sclerosis and effects of corticotherapy during relapse. Mult Scler 21(12):1533–1545PubMedCrossRefGoogle Scholar
  185. 185.
    Esposito M et al (2010) IL-17- and IFN-gamma-secreting Foxp3+ T cells infiltrate the target tissue in experimental autoimmunity. J Immunol 185(12):7467–7473PubMedCrossRefGoogle Scholar
  186. 186.
    Li X et al (2014) Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158(4):734–748PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Du W et al (2013) Foxp3+ Treg expanded from patients with established diabetes reduce Helios expression while retaining normal function compared to healthy individuals. PLoS One 8(2):e56209PubMedPubMedCentralCrossRefGoogle Scholar
  188. 188.
    Graves CL et al (2016) Intestinal epithelial cell regulation of adaptive immune dysfunction in human type 1 diabetes. Front Immunol 7:679PubMedGoogle Scholar
  189. 189.
    Tan TG, Mathis D, Benoist C (2016) Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes. Proc Natl Acad Sci U S A 113(49):14103–14108PubMedPubMedCentralCrossRefGoogle Scholar
  190. 190.
    Kornete M, Sgouroudis E, Piccirillo CA (2012) ICOS-dependent homeostasis and function of Foxp3+ regulatory T cells in islets of nonobese diabetic mice. J Immunol 188(3):1064–1074PubMedCrossRefGoogle Scholar
  191. 191.
    Marwaha AK et al (2010) Cutting edge: increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J Immunol 185(7):3814–3818PubMedCrossRefGoogle Scholar
  192. 192.
    Kumar P, Subramaniyam G (2015) Molecular underpinnings of Th17 immune-regulation and their implications in autoimmune diabetes. Cytokine 71(2):366–376PubMedCrossRefGoogle Scholar
  193. 193.
    Visperas A, Vignali DA (2016) Are regulatory T cells defective in type 1 diabetes and can we fix them? J Immunol 197(10):3762–3770PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Ferreira RC et al (2017) Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity. J Autoimmun 84:75–86PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    D'Hennezel E, Kornete M, Piccirillo CA (2010) IL-2 as a therapeutic target for the restoration of Foxp3+ regulatory T cell function in organ-specific autoimmunity: implications in pathophysiology and translation to human disease. J Transl Med 8:113PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Jeker LT et al (2012) MicroRNA 10a marks regulatory T cells. PLoS One 7(5):e36684PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Bovenschen HJ et al (2011) Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol 131(9):1853–1860PubMedCrossRefGoogle Scholar
  198. 198.
    Gatzka M, Scharffetter-Kochanek K (2015) T-cell plasticity in inflammatory skin diseases--the good, the bad, and the chameleons. J Dtsch Dermatol Ges 13(7):647–652PubMedGoogle Scholar
  199. 199.
    Fiocco U et al (2015) Transcriptional network profile on synovial fluid T cells in psoriatic arthritis. Clin Rheumatol 34(9):1571–1580PubMedCrossRefGoogle Scholar
  200. 200.
    Yang L et al (2016) Impaired function of regulatory T cells in patients with psoriasis is mediated by phosphorylation of STAT3. J Dermatol Sci 81(2):85–92PubMedCrossRefGoogle Scholar
  201. 201.
    Singh K et al (2013) Reduced CD18 levels drive regulatory T cell conversion into Th17 cells in the CD18hypo PL/J mouse model of psoriasis. J Immunol 190(6):2544–2553PubMedCrossRefGoogle Scholar
  202. 202.
    Soler DC, McCormick TS (2011) The dark side of regulatory T cells in psoriasis. J Invest Dermatol 131(9):1785–1786PubMedPubMedCentralCrossRefGoogle Scholar
  203. 203.
    He X et al (2014) Targeting PKC in human T cells using sotrastaurin (AEB071) preserves regulatory T cells and prevents IL-17 production. J Invest Dermatol 134(4):975–983PubMedCrossRefGoogle Scholar
  204. 204.
    Soler DC et al (2013) Psoriasis patients exhibit impairment of the high potency CCR5(+) T regulatory cell subset. Clin Immunol 149(1):111–118PubMedCrossRefGoogle Scholar
  205. 205.
    Zhang HY et al (2015) Target tissue ectoenzyme CD39/CD73-expressing Foxp3+ regulatory T cells in patients with psoriasis. Clin Exp Dermatol 40(2):182–191PubMedCrossRefGoogle Scholar
  206. 206.
    Liu X et al (2013) Elevated levels of CD4(+)CD25(+)FoxP3(+) T cells in systemic sclerosis patients contribute to the secretion of IL-17 and immunosuppression dysfunction. PLoS One 8(6):e64531PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Almanzar G et al (2016) Disease manifestation and inflammatory activity as modulators of Th17/Treg balance and RORC/FoxP3 methylation in systemic sclerosis. Int Arch Allergy Immunol 171(2):141–154PubMedCrossRefGoogle Scholar
  208. 208.
    Wang YY et al (2014) DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. Br J Dermatol 171(1):39–47PubMedCrossRefGoogle Scholar
  209. 209.
    Alexander T et al (2013) Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus. Ann Rheum Dis 72(9):1549–1558PubMedCrossRefGoogle Scholar
  210. 210.
    Katsuyama E et al (2017) Downregulation of miR-200a-3p, targeting CtBP2 complex, is involved in the hypoproduction of IL-2 in systemic lupus erythematosus-derived T cells. J Immunol 198(11):4268–4276PubMedCrossRefGoogle Scholar
  211. 211.
    Frank-Bertoncelj M, Gay S (2014) The epigenome of synovial fibroblasts: an underestimated therapeutic target in rheumatoid arthritis. Arthritis Res Ther 16(3):117PubMedPubMedCentralCrossRefGoogle Scholar
  212. 212.
    Park JS et al (2014) STA-21, a promising STAT-3 inhibitor that reciprocally regulates Th17 and Treg cells, inhibits osteoclastogenesis in mice and humans and alleviates autoimmune inflammation in an experimental model of rheumatoid arthritis. Arthritis Rheumatol 66(4):918–929PubMedCrossRefGoogle Scholar
  213. 213.
    Caplazi P et al (2015) Mouse models of rheumatoid arthritis. Vet Pathol 52(5):819–826PubMedCrossRefGoogle Scholar
  214. 214.
    Cooles FA, Isaacs JD, Anderson AE (2013) Treg cells in rheumatoid arthritis: an update. Curr Rheumatol Rep 15(9):352PubMedCrossRefGoogle Scholar
  215. 215.
    Shalini PU et al (2015) A study on FoxP3 and Tregs in paired samples of peripheral blood and synovium in rheumatoid arthritis. Cent Eur J Immunol 40(4):431–436Google Scholar
  216. 216.
    Alunno A et al (2015) Altered immunoregulation in rheumatoid arthritis: the role of regulatory T cells and proinflammatory Th17 cells and therapeutic implications. Mediat Inflamm 2015:751793Google Scholar
  217. 217.
    Noack M, Miossec P (2014) Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 13(6):668–677PubMedCrossRefGoogle Scholar
  218. 218.
    Jimeno R et al (2015) Th17 polarization of memory Th cells in early arthritis: the vasoactive intestinal peptide effect. J Leukoc Biol 98(2):257–269PubMedCrossRefGoogle Scholar
  219. 219.
    Li N et al (2015) The abnormal expression of CCR4 and CCR6 on Tregs in rheumatoid arthritis. Int J Clin Exp Med 8(9):15043–15053PubMedPubMedCentralGoogle Scholar
  220. 220.
    Dendrou CA, Fugger L, Friese MA (2015) Immunopathology of multiple sclerosis. Nat Rev Immunol 15(9):545–558CrossRefGoogle Scholar
  221. 221.
    Bhargava P, Mowry EM (2014) Gut microbiome and multiple sclerosis. Curr Neurol Neurosci Rep 14(10):492PubMedCrossRefGoogle Scholar
  222. 222.
    Karussis D (2014) The diagnosis of multiple sclerosis and the various related demyelinating syndromes: a critical review. J Autoimmun 48-49:134–142PubMedCrossRefGoogle Scholar
  223. 223.
    Noori-Zadeh A et al (2016) Regulatory T cell number in multiple sclerosis patients: a meta-analysis. Mult Scler Relat Disord 5:73–76PubMedCrossRefGoogle Scholar
  224. 224.
    Pennisi M et al (2013) Agent based modeling of Treg-Teff cross regulation in relapsing-remitting multiple sclerosis. BMC Bioinf 14(Suppl 16):S9CrossRefGoogle Scholar
  225. 225.
    Etesam Z et al (2016) Altered expression of specific transcription factors of Th17 (RORgammat, RORalpha) and Treg lymphocytes (FOXP3) by peripheral blood mononuclear cells from patients with multiple sclerosis. J Mol Neurosci 60(1):94–101PubMedCrossRefGoogle Scholar
  226. 226.
    Naghavian R et al (2015) miR-141 and miR-200a, revelation of new possible players in modulation of Th17/Treg differentiation and pathogenesis of multiple sclerosis. PLoS One 10(5):e0124555PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    McPherson RC et al (2015) T-bet expression by Foxp3(+) T regulatory cells is not essential for their suppressive function in CNS autoimmune disease or colitis. Front Immunol 6:69PubMedPubMedCentralCrossRefGoogle Scholar
  228. 228.
    Gao Y et al (2015) Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. Proc Natl Acad Sci U S A 112(25):E3246–E3254PubMedPubMedCentralCrossRefGoogle Scholar
  229. 229.
    Segal BM (2012) The unwavering commitment of regulatory T cells in the suppression of autoimmune encephalomyelitis: another aspect of immune privilege in the CNS. Eur J Immunol 42(5):1102–1105PubMedCrossRefGoogle Scholar
  230. 230.
    O'Connor RA et al (2012) Foxp3(+) Treg cells in the inflamed CNS are insensitive to IL-6-driven IL-17 production. Eur J Immunol 42(5):1174–1179PubMedCrossRefGoogle Scholar
  231. 231.
    Xie Z, Chang C, Zhou Z (2014) Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol 47(2):174–192PubMedCrossRefGoogle Scholar
  232. 232.
    Simmons K, Michels AW (2014) Lessons from type 1 diabetes for understanding natural history and prevention of autoimmune disease. Rheum Dis Clin N Am 40(4):797–811CrossRefGoogle Scholar
  233. 233.
    ElEssawy B, Li XC (2015) Type 1 diabetes and T regulatory cells. Pharmacol Res 98:22–30PubMedCrossRefGoogle Scholar
  234. 234.
    Serr I et al (2014) Treg vaccination in autoimmune type 1 diabetes. BioDrugs 28(1):7–16PubMedCrossRefGoogle Scholar
  235. 235.
    Bluestone JA et al (2015) Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med 7(315):315ra189PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Kornete M et al (2015) Th1-Like ICOS+ Foxp3+ Treg cells preferentially express CXCR3 and home to beta-islets during pre-diabetes in BDC2.5 NOD Mice. PLoS One 10(5):e0126311PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Jiang S, Hinchliffe TE, Wu T (2015) Biomarkers of an autoimmune skin disease—psoriasis. Genomics Proteomics Bioinformatics 13(4):224–233PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Boehncke WH, Schon MP (2015) Psoriasis. Lancet 386(9997):983–994PubMedCrossRefGoogle Scholar
  239. 239.
    Elhai M et al (2015) Systemic sclerosis: recent insights. Joint Bone Spine 82(3):148–153PubMedCrossRefGoogle Scholar
  240. 240.
    Stern EP, Denton CP (2015) The pathogenesis of systemic sclerosis. Rheum Dis Clin N Am 41(3):367–382CrossRefGoogle Scholar
  241. 241.
    Oka T et al (2017) CXCL17 attenuates imiquimod-induced psoriasis-like skin inflammation by recruiting myeloid-derived suppressor cells and regulatory T cells. J Immunol 198(10):3897–3908PubMedCrossRefGoogle Scholar
  242. 242.
    Kataoka H et al (2015) Decreased expression of Runx1 and lowered proportion of Foxp3(+) CD25(+) CD4(+) regulatory T cells in systemic sclerosis. Mod Rheumatol 25(1):90–95PubMedCrossRefGoogle Scholar
  243. 243.
    Mattozzi C et al (2013) Importance of regulatory T cells in the pathogenesis of psoriasis: review of the literature. Dermatology 227(2):134–145PubMedCrossRefGoogle Scholar
  244. 244.
    Papp G et al (2012) The effects of extracorporeal photochemotherapy on T cell activation and regulatory mechanisms in patients with systemic sclerosis. Clin Rheumatol 31(9):1293–1299PubMedCrossRefGoogle Scholar
  245. 245.
    Cripps JG et al (2012) Liver inflammation in a mouse model of Th1 hepatitis despite the absence of invariant NKT cells or the Th1 chemokine receptors CXCR3 and CCR5. Lab Invest 92(10):1461–1471PubMedPubMedCentralCrossRefGoogle Scholar
  246. 246.
    Kim SM et al (2014) 27-Hydroxycholesterol and 7alpha-hydroxycholesterol trigger a sequence of events leading to migration of CCR5-expressing Th1 lymphocytes. Toxicol Appl Pharmacol 274(3):462–470PubMedCrossRefGoogle Scholar
  247. 247.
    Chen L et al (2013) mTORC2-PKBalpha/Akt1 Serine 473 phosphorylation axis is essential for regulation of FOXP3 Stability by chemokine CCL3 in psoriasis. J Invest Dermatol 133(2):418–428PubMedCrossRefGoogle Scholar
  248. 248.
    Komai-Koma M et al (2007) IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol 37(10):2779–2786PubMedCrossRefGoogle Scholar
  249. 249.
    Yu C, Gershwin ME, Chang C (2014) Diagnostic criteria for systemic lupus erythematosus: a critical review. J Autoimmun 48-49:10–13PubMedCrossRefGoogle Scholar
  250. 250.
    Mohan C, Putterman C (2015) Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol 11(6):329–341PubMedCrossRefGoogle Scholar
  251. 251.
    Ohl K, Tenbrock K (2015) Regulatory T cells in systemic lupus erythematosus. Eur J Immunol 45(2):344–355PubMedCrossRefGoogle Scholar
  252. 252.
    Golding A et al (2013) The percentage of FoxP3+Helios+ Treg cells correlates positively with disease activity in systemic lupus erythematosus. Arthritis Rheum 65(11):2898–2906PubMedPubMedCentralCrossRefGoogle Scholar
  253. 253.
    Kaser T et al (2015) Natural and inducible Tregs in swine: helios expression and functional properties. Dev Comp Immunol 49(2):323–331PubMedCrossRefGoogle Scholar
  254. 254.
    Larkin JR et al (2013) Regulation of interferon gamma signaling by suppressors of cytokine signaling and regulatory T cells. Front Immunol 4:469PubMedPubMedCentralCrossRefGoogle Scholar
  255. 255.
    Taleb S, Tedgui A, Mallat Z (2015) IL-17 and Th17 cells in atherosclerosis: subtle and contextual roles. Arterioscler Thromb Vasc Biol 35(2):258–264PubMedCrossRefPubMedCentralGoogle Scholar
  256. 256.
    Melzer S et al (2015) Nanoparticle uptake by macrophages in vulnerable plaques for atherosclerosis diagnosis. J Biophotonics 8(11–12):871–883PubMedCrossRefPubMedCentralGoogle Scholar
  257. 257.
    Matsuura E et al (2014) Is atherosclerosis an autoimmune disease? BMC Med 12:47PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Hasib L et al (2016) Functional and homeostatic defects of regulatory T cells in patients with coronary artery disease. J Intern Med 279(1):63–77PubMedCrossRefPubMedCentralGoogle Scholar
  259. 259.
    Cosmi L et al (2014) Th17 plasticity: pathophysiology and treatment of chronic inflammatory disorders. Curr Opin Pharmacol 17:12–16PubMedCrossRefPubMedCentralGoogle Scholar
  260. 260.
    Ueno A et al (2015) Th17 plasticity and its changes associated with inflammatory bowel disease. World J Gastroenterol 21(43):12283–12295PubMedPubMedCentralCrossRefGoogle Scholar
  261. 261.
    Chen Y et al (2017) IFN-gamma-expressing Th17 cells are required for development of severe ocular surface autoimmunity. J Immunol 199(3):1163–1169PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of Pharmacy, Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia MedicaNanjing University of Chinese MedicineNanjingPeople’s Republic of China

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