Skip to main content
SpringerLink
Log in

Ubiquitous points of control over regulatory T cells

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

Posttranslational modification by ubiquitin tagging is crucial for regulating the stability, activity and cellular localization of many target proteins involved in processes including DNA repair, cell cycle progression, protein quality control, and signal transduction. It has long been appreciated that ubiquitin-mediated events are important for certain signaling pathways leading to leukocyte activation and the stimulation of effector function. Now it is clear that the activities of molecules and pathways central to immune regulation are also modified and controlled by ubiquitin tagging. Among the mechanisms of immune control, regulatory T cells (or Tregs) are themselves particularly sensitive to such regulation. E3 ligases and deubiquitinases both influence Tregs through their effects on the signaling pathways pertinent to these cells or through the direct, posttranslational regulation of Foxp3. In this review, we will summarize and discuss several examples of ubiquitin-mediated control over multiple aspects of Treg biology including the generation, function and phenotypic fidelity of these cells. Fully explored and exploited, these potential opportunities for Treg modulation may lead to novel immunotherapies for both positive and negative fine-tuning of immune restraint.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    CAS  PubMed  Google Scholar 

  2. Vignali DA, Collison LW, Workman CJ (2008) How regulatory T cells work. Nat Rev Immunol 8:523–532

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Hori S (2011) Stability of regulatory T-cell lineage. Adv Immunol 112:1–24

    PubMed  Google Scholar 

  4. Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D et al (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30:899–911

    CAS  PubMed  Google Scholar 

  5. Koch MA, Tucker-Heard G, Perdue NR, Killebrew JR, Urdahl KB, Campbell DJ (2009) The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10:595–602

    CAS  PubMed Central  PubMed  Google Scholar 

  6. Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, Pritchard GH, Silver JS, Bouladoux N, Stumhofer JS et al (2012) The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37:511–523

    PubMed Central  PubMed  Google Scholar 

  7. Sharma MD, Huang L, Choi JH, Lee EJ, Wilson JM, Lemos H, Pan F, Blazar BR, Pardoll DM, Mellor AL et al (2013) An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38:998–1012

    CAS  PubMed  Google Scholar 

  8. Josefowicz SZ, Niec RE, Kim HY, Treuting P, Chinen T, Zheng Y, Umetsu DT, Rudensky AY (2012) Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482:395–399

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Williams LM, Rudensky AY (2007) Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 8:277–284

    CAS  PubMed  Google Scholar 

  10. Pan F, Yu H, Dang EV, Barbi J, Pan X, Grosso JF, Jinasena D, Sharma SM, McCadden EM, Getnet D et al (2009) Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 325:1142–1146

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Fu W, Ergun A, Lu T, Hill JA, Haxhinasto S, Fassett MS, Gazit R, Adoro S, Glimcher L, Chan S et al (2012) A multiply redundant genetic switch ‘locks in’ the transcriptional signature of regulatory T cells. Nat Immunol 13:972–980

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Zheng Y, Chaudhry A, Kas A, deRoos P, Kim JM, Chu TT, Corcoran L, Treuting P, Klein U, Rudensky AY (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458:351–356

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Darce J, Rudra D, Li L, Nishio J, Cipolletta D, Rudensky AY, Mathis D, Benoist C (2012) An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes. Immunity 36:731–741

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Bettini ML, Pan F, Bettini M, Finkelstein D, Rehg JE, Floess S, Bell BD, Ziegler SF, Huehn J, Pardoll DM et al (2012) Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity 36:717–730

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Kerscher O, Felberbaum R, Hochstrasser M (2006) Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu Rev Cell Dev Biol 22:159–180

    CAS  PubMed  Google Scholar 

  16. Hershko A, Ciechanover A (1998) The ubiquitin system. Annu Rev Biochem 67:425–479

    CAS  PubMed  Google Scholar 

  17. Jackson PK, Eldridge AG, Freed E, Furstenthal L, Hsu JY, Kaiser BK, Reimann JD (2000) The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 10:429–439

    CAS  PubMed  Google Scholar 

  18. Gao M, Karin M (2005) Regulating the regulators: control of protein ubiquitination and ubiquitin-like modifications by extracellular stimuli. Mol Cell 19:581–593

    CAS  PubMed  Google Scholar 

  19. Zinngrebe J, Montinaro A, Peltzer N, Walczak H (2014) Ubiquitin in the immune system. EMBO Rep 15:28–45

    PubMed  Google Scholar 

  20. Komander D, Clague MJ, Urbe S (2009) Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol 10:550–563

    CAS  PubMed  Google Scholar 

  21. Reyes-Turcu FE, Ventii KH, Wilkinson KD (2009) Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes. Annu Rev Biochem 78:363–397

    CAS  PubMed  Google Scholar 

  22. Schmitt EG, Williams CB (2013) Generation and function of induced regulatory T cells. Front Immunol 4:152

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Qiao G, Zhao Y, Li Z, Tang PQ, Langdon WY, Yang T, Zhang J (2013) T cell activation threshold regulated by E3 ubiquitin ligase Cbl-b determines fate of inducible regulatory T cells. J Immunol 191:632–639

    CAS  PubMed  Google Scholar 

  24. Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A et al (2000) Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature 403:211–216

    CAS  PubMed  Google Scholar 

  25. Wohlfert EA, Callahan MK, Clark RB (2004) Resistance to CD4 + CD25+ regulatory T cells and TGF-beta in Cbl-b−/− mice. J Immunol 173:1059–1065

    CAS  PubMed  Google Scholar 

  26. Adams CO, Housley WJ, Bhowmick S, Cone RE, Rajan TV, Forouhar F, Clark RB (2010) Cbl-b(−/−) T cells demonstrate in vivo resistance to regulatory T cells but a context-dependent resistance to TGF-beta. J Immunol 185:2051–2058

    CAS  PubMed  Google Scholar 

  27. Haxhinasto S, Mathis D, Benoist C (2008) The AKT-mTOR axis regulates de novo differentiation of CD4 + Foxp3+ cells. J Exp Med 205:565–574

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O’Connor E et al (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 105:7797–7802

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Ouyang W, Beckett O, Ma Q, Paik JH, DePinho RA, Li MO (2010) Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol 11:618–627

    CAS  PubMed  Google Scholar 

  30. Harada Y, Elly C, Ying G, Paik JH, DePinho RA, Liu YC (2010) Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med 207:1381–1391

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Fang D, Wang HY, Fang N, Altman Y, Elly C, Liu YC (2001) Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J Biol Chem 276:4872–4878

    CAS  PubMed  Google Scholar 

  32. Fang D, Liu YC (2001) Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat Immunol 2:870–875

    CAS  PubMed  Google Scholar 

  33. Wohlfert EA, Gorelik L, Mittler R, Flavell RA, Clark RB (2006) Cutting edge: deficiency in the E3 ubiquitin ligase Cbl-b results in a multifunctional defect in T cell TGF-beta sensitivity in vitro and in vivo. J Immunol 176:1316–1320

    CAS  PubMed  Google Scholar 

  34. Gruber T, Hinterleitner R, Hermann-Kleiter N, Meisel M, Kleiter I, Wang CM, Viola A, Pfeifhofer-Obermair C, Baier G (2013) Cbl-b mediates TGFbeta sensitivity by downregulating inhibitory SMAD7 in primary T cells. J Mol Cell Biol 5:358–368

    CAS  PubMed  Google Scholar 

  35. Dominitzki S, Fantini MC, Neufert C, Nikolaev A, Galle PR, Scheller J, Monteleone G, Rose-John S, Neurath MF, Becker C (2007) Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4 + CD25 T cells. J Immunol 179:2041–2045

    CAS  PubMed  Google Scholar 

  36. Venuprasad K, Elly C, Gao M, Salek-Ardakani S, Harada Y, Luo JL, Yang C, Croft M, Inoue K, Karin M et al (2006) Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. J Clin Invest 116:1117–1126

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Bai Y, Yang C, Hu K, Elly C, Liu YC (2004) Itch E3 ligase-mediated regulation of TGF-beta signaling by modulating smad2 phosphorylation. Mol Cell 15:825–831

    CAS  PubMed  Google Scholar 

  38. Venuprasad K, Huang H, Harada Y, Elly C, Subramaniam M, Spelsberg T, Su J, Liu YC (2008) The E3 ubiquitin ligase Itch regulates expression of transcription factor Foxp3 and airway inflammation by enhancing the function of transcription factor TIEG1. Nat Immunol 9:245–253

    CAS  PubMed Central  PubMed  Google Scholar 

  39. Peng DJ, Zeng M, Muromoto R, Matsuda T, Shimoda K, Subramaniam M, Spelsberg TC, Wei WZ, Venuprasad K (2011) Noncanonical K27-linked polyubiquitination of TIEG1 regulates Foxp3 expression and tumor growth. J Immunol 186:5638–5647

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Wang D, Qin H, Du W, Shen YW, Lee WH, Riggs AD, Liu CP (2012) Inhibition of S-phase kinase-associated protein 2 (Skp2) reprograms and converts diabetogenic T cells to Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A 109:9493–9498

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Lee YK, Mukasa R, Hatton RD, Weaver CT (2009) Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol 21:274–280

    CAS  PubMed  Google Scholar 

  42. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    CAS  PubMed  Google Scholar 

  43. Nakayama K, Frew IJ, Hagensen M, Skals M, Habelhah H, Bhoumik A, Kadoya T, Erdjument-Bromage H, Tempst P, Frappell PB et al (2004) Siah2 regulates stability of prolyl-hydroxylases, controls HIF1alpha abundance, and modulates physiological responses to hypoxia. Cell 117:941–952

    CAS  PubMed  Google Scholar 

  44. Semenza GL (2007) Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007: cm8. doi:10.1126/stke.4072007cm8

  45. Lecker SH, Goldberg AL, Mitch WE (2006) Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol 17:1807–1819

    CAS  PubMed  Google Scholar 

  46. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR et al (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146:772–784

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367–1376

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Kim JS, Sklarz T, Banks LB, Gohil M, Waickman AT, Skuli N, Krock BL, Luo CT, Hu W, Pollizzi KN et al (2013) Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat Immunol 14:611–618

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP et al (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109:E2784–E2793

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Burocchi A, Colombo MP, Piconese S (2013) Convergences and divergences of thymus- and peripherally derived regulatory T cells in cancer. Front Immunol 4:247

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Wang C, Lee JH, Kim CH (2012) Optimal population of FoxP3+ T cells in tumors requires an antigen priming-dependent trafficking receptor switch. PLoS One 7:e30793

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Hindley JP, Ferreira C, Jones E, Lauder SN, Ladell K, Wynn KK, Betts GJ, Singh Y, Price DA, Godkin AJ et al (2011) Analysis of the T-cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res 71:736–746

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Luo W, Zhong J, Chang R, Hu H, Pandey A, Semenza GL (2010) Hsp70 and CHIP selectively mediate ubiquitination and degradation of hypoxia-inducible factor (HIF)-1alpha but Not HIF-2alpha. J Biol Chem 285:3651–3663

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Ikejiri A, Nagai S, Goda N, Kurebayashi Y, Osada-Oka M, Takubo K, Suda T, Koyasu S (2012) Dynamic regulation of Th17 differentiation by oxygen concentrations. Int Immunol 24:137–146

    CAS  PubMed  Google Scholar 

  55. Eckert DJ, Malhotra A (2008) Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc 5:144–153

    PubMed Central  PubMed  Google Scholar 

  56. Ye J, Liu H, Zhang G, Li P, Wang Z, Huang S, Yang Q, Li Y (2012) The treg/th17 imbalance in patients with obstructive sleep apnoea syndrome. Mediat Inflamm 2012:815308

    Google Scholar 

  57. Josefowicz SZ, Rudensky A (2009) Control of regulatory T cell lineage commitment and maintenance. Immunity 30:616–625

    CAS  PubMed  Google Scholar 

  58. Gupta S, Manicassamy S, Vasu C, Kumar A, Shang W, Sun Z (2008) Differential requirement of PKC-theta in the development and function of natural regulatory T cells. Mol Immunol 46:213–224

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Barnes MJ, Krebs P, Harris N, Eidenschenk C, Gonzalez-Quintial R, Arnold CN, Crozat K, Sovath S, Moresco EM, Theofilopoulos AN et al (2009) Commitment to the regulatory T cell lineage requires CARMA1 in the thymus but not in the periphery. PLoS Biol 7:e51

    PubMed  Google Scholar 

  60. Schmidt-Supprian M, Tian J, Grant EP, Pasparakis M, Maehr R, Ovaa H, Ploegh HL, Coyle AJ, Rajewsky K (2004) Differential dependence of CD4 + CD25+ regulatory and natural killer-like T cells on signals leading to NF-kappaB activation. Proc Natl Acad Sci U S A 101:4566–4571

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Medoff BD, Sandall BP, Landry A, Nagahama K, Mizoguchi A, Luster AD, Xavier RJ (2009) Differential requirement for CARMA1 in agonist-selected T-cell development. Eur J Immunol 39:78–84

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Paul S, Schaefer BC (2013) A new look at T cell receptor signaling to nuclear factor-kappaB. Trends Immunol 34:269–281

    CAS  PubMed  Google Scholar 

  63. Isomura I, Palmer S, Grumont RJ, Bunting K, Hoyne G, Wilkinson N, Banerjee A, Proietto A, Gugasyan R, Wu L et al (2009) c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J Exp Med 206:3001–3014

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Long M, Park SG, Strickland I, Hayden MS, Ghosh S (2009) Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31:921–931

    CAS  PubMed  Google Scholar 

  65. Ruan Q, Kameswaran V, Tone Y, Li L, Liou HC, Greene MI, Tone M, Chen YH (2009) Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 31:932–940

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Vang KB, Yang J, Pagan AJ, Li LX, Wang J, Green JM, Beg AA, Farrar MA (2010) Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J Immunol 184:4074–4077

    CAS  PubMed Central  PubMed  Google Scholar 

  67. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Deenick EK, Elford AR, Pellegrini M, Hall H, Mak TW, Ohashi PS (2010) c-Rel but not NF-kappaB1 is important for T regulatory cell development. Eur J Immunol 40:677–681

    CAS  PubMed  Google Scholar 

  69. Visekruna A, Huber M, Hellhund A, Bothur E, Reinhard K, Bollig N, Schmidt N, Joeris T, Lohoff M, Steinhoff U (2010) c-Rel is crucial for the induction of Foxp3(+) regulatory CD4(+) T cells but not T(H)17 cells. Eur J Immunol 40:671–676

    CAS  PubMed  Google Scholar 

  70. Grigoriadis G, Vasanthakumar A, Banerjee A, Grumont R, Overall S, Gleeson P, Shannon F, Gerondakis S (2011) c-Rel controls multiple discrete steps in the thymic development of Foxp3+ CD4 regulatory T cells. PLoS One 6:e26851

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Molinero LL, Miller ML, Evaristo C, Alegre ML (2011) High TCR stimuli prevent induced regulatory T cell differentiation in a NF-kappaB-dependent manner. J Immunol 186:4609–4617

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Zanin-Zhorov A, Ding Y, Kumari S, Attur M, Hippen KL, Brown M, Blazar BR, Abramson SB, Lafaille JJ, Dustin ML (2010) Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 328:372–376

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Chen E, Hrdlickova R, Nehyba J, Longo DL, Bose HR Jr, Li CC (1998) Degradation of proto-oncoprotein c-Rel by the ubiquitin-proteasome pathway. J Biol Chem 273:35201–35207

    CAS  PubMed  Google Scholar 

  74. Chang M, Jin W, Chang JH, Xiao Y, Brittain GC, Yu J, Zhou X, Wang YH, Cheng X, Li P et al (2011) The ubiquitin ligase Peli1 negatively regulates T cell activation and prevents autoimmunity. Nat Immunol 12:1002–1009

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Tze LE, Horikawa K, Domaschenz H, Howard DR, Roots CM, Rigby RJ, Way DA, Ohmura-Hoshino M, Ishido S, Andoniou CE et al (2011) CD83 increases MHC II and CD86 on dendritic cells by opposing IL-10-driven MARCH1-mediated ubiquitination and degradation. J Exp Med 208:149–165

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Oh J, Wu N, Baravalle G, Cohn B, Ma J, Lo B, Mellman I, Ishido S, Anderson M, Shin JS (2013) MARCH1-mediated MHCII ubiquitination promotes dendritic cell selection of natural regulatory T cells. J Exp Med 210:1069–1077

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Inoue J, Gohda J, Akiyama T (2007) Characteristics and biological functions of TRAF6. Adv Exp Med Biol 597:72–79

    PubMed  Google Scholar 

  78. Akiyama T, Maeda S, Yamane S, Ogino K, Kasai M, Kajiura F, Matsumoto M, Inoue J (2005) Dependence of self-tolerance on TRAF6-directed development of thymic stroma. Science 308:248–251

    CAS  PubMed  Google Scholar 

  79. Chiffoleau E, Kobayashi T, Walsh MC, King CG, Walsh PT, Hancock WW, Choi Y, Turka LA (2003) TNF receptor-associated factor 6 deficiency during hemopoiesis induces Th2-polarized inflammatory disease. J Immunol 171:5751–5759

    CAS  PubMed  Google Scholar 

  80. Shimo Y, Yanai H, Ohshima D, Qin J, Motegi H, Maruyama Y, Hori S, Inoue J, Akiyama T (2011) TRAF6 directs commitment to regulatory T cells in thymocytes. Genes Cells 16:437–447

    CAS  PubMed  Google Scholar 

  81. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  82. Duarte JH, Zelenay S, Bergman ML, Martins AC, Demengeot J (2009) Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol 39:948–955

    CAS  PubMed  Google Scholar 

  83. Yang XO, Nurieva R, Martinez GJ, Kang HS, Chung Y, Pappu BP, Shah B, Chang SH, Schluns KS, Watowich SS et al (2008) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29:44–56

    CAS  PubMed Central  PubMed  Google Scholar 

  84. 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

    CAS  PubMed  Google Scholar 

  85. 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

    CAS  PubMed  Google Scholar 

  86. Bailey-Bucktrout SL, Martinez-Llordella M, Zhou X, Anthony B, Rosenthal W, Luche H, Fehling HJ, Bluestone JA (2013) Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39:949–962

    CAS  PubMed  Google Scholar 

  87. 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

    CAS  PubMed  Google Scholar 

  88. Laurence A, Amarnath S, Mariotti J, Kim YC, Foley J, Eckhaus M, O’Shea JJ, Fowler DH (2012) STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 37:209–222

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Duhen T, Duhen R, Lanzavecchia A, Sallusto F, Campbell DJ (2012) Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 119:4430–4440

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Zhang P, Tey SK, Koyama M, Kuns RD, Olver SD, Lineburg KE, Lor M, Teal BE, Raffelt NC, Raju J et al (2013) Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo. J Immunol 191:5291–5303

    CAS  PubMed  Google Scholar 

  91. Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J et al (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501:252–256

    CAS  PubMed  Google Scholar 

  92. Chen Q, Kim YC, Laurence A, Punkosdy GA, Shevach EM (2011) IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J Immunol 186:6329–6337

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, Deroos P, Liu H, Cross JR, Pfeffer K, Coffer PJ et al (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. doi:10.1038/nature12726

    PubMed  Google Scholar 

  94. Zhang R, Huynh A, Whitcher G, Chang J, Maltzman JS, Turka LA (2013) An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest 123:580–593

    CAS  PubMed Central  PubMed  Google Scholar 

  95. Nie H, Zheng Y, Li R, Guo TB, He D, Fang L, Liu X, Xiao L, Chen X, Wan B et al (2013) Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med 19:322–328

    CAS  PubMed  Google Scholar 

  96. van Loosdregt J, Fleskens V, Tiemessen MM, Mokry M, van Boxtel R, Meerding J, Pals CE, Kurek D, Baert MR, Delemarre EM et al (2013) Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity 39:298–310

    PubMed  Google Scholar 

  97. van der Touw W, Cravedi P, Kwan WH, Paz-Artal E, Merad M, Heeger PS (2013) Cutting edge: receptors for C3a and C5a modulate stability of alloantigen-reactive induced regulatory T cells. J Immunol 190:5921–5925

    PubMed  Google Scholar 

  98. Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE (2006) TNF downmodulates the function of human CD4 + CD25hi T-regulatory cells. Blood 108:253–261

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Strainic MG, Shevach EM, An F, Lin F, Medof ME (2013) Absence of signaling into CD4(+) cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3(+) regulatory T cells. Nat Immunol 14:162–171

    CAS  PubMed  Google Scholar 

  100. Schaer DA (2013) GITR pathway activation abrogates tumor immune suppression through loss of regulatory T-cell lineage stability. Cancer Immunol Res 1:320–331

    CAS  Google Scholar 

  101. Liu G, Burns S, Huang G, Boyd K, Proia RL, Flavell RA, Chi H (2009) The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat Immunol 10:769–777

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Kwan WH, van der Touw W, Paz-Artal E, Li MO, Heeger PS (2013) Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells. J Exp Med 210:257–268

    CAS  PubMed Central  PubMed  Google Scholar 

  103. van Loosdregt J, Vercoulen Y, Guichelaar T, Gent YY, Beekman JM, van Beekum O, Brenkman AB, Hijnen DJ, Mutis T, Kalkhoven E et al (2010) Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115:965–974

    PubMed  Google Scholar 

  104. Samanta A, Li B, Song X, Bembas K, Zhang G, Katsumata M, Saouaf SJ, Wang Q, Hancock WW, Shen Y et al (2008) TGF-beta and IL-6 signals modulate chromatin binding and promoter occupancy by acetylated FOXP3. Proc Natl Acad Sci U S A 105:14023–14027

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Jin HS, Park Y, Elly C, Liu YC (2013) Itch expression by Treg cells controls Th2 inflammatory responses. J Clin Invest 123:4923–4934

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Fukushima T, Matsuzawa S, Kress CL, Bruey JM, Krajewska M, Lefebvre S, Zapata JM, Ronai Z, Reed JC (2007) Ubiquitin-conjugating enzyme Ubc13 is a critical component of TNF receptor-associated factor (TRAF)-mediated inflammatory responses. Proc Natl Acad Sci U S A 104:6371–6376

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Chang JH, Xiao Y, Hu H, Jin J, Yu J, Zhou X, Wu X, Johnson HM, Akira S, Pasparakis M et al (2012) Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 13:481–490

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Takahashi R, Nishimoto S, Muto G, Sekiya T, Tamiya T, Kimura A, Morita R, Asakawa M, Chinen T, Yoshimura A (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 208:2055–2067

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Kriegel MA, Rathinam C, Flavell RA (2009) E3 ubiquitin ligase GRAIL controls primary T cell activation and oral tolerance. Proc Natl Acad Sci U S A 106:16770–16775

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Nurieva RI, Zheng S, Jin W, Chung Y, Zhang Y, Martinez GJ, Reynolds JM, Wang SL, Lin X, Sun SC et al (2010) The E3 ubiquitin ligase GRAIL regulates T cell tolerance and regulatory T cell function by mediating T cell receptor-CD3 degradation. Immunity 32:670–680

    CAS  PubMed Central  PubMed  Google Scholar 

  111. MacKenzie DA, Schartner J, Lin J, Timmel A, Jennens-Clough M, Fathman CG, Seroogy CM (2007) GRAIL is up-regulated in CD4+ CD25+ T regulatory cells and is sufficient for conversion of T cells to a regulatory phenotype. J Biol Chem 282:9696–9702

    CAS  PubMed  Google Scholar 

  112. Chattopadhyay G, Shevach EM (2013) Antigen-specific induced T regulatory cells impair dendritic cell function via an IL-10/MARCH1-dependent mechanism. J Immunol 191:5875–5884

    CAS  PubMed  Google Scholar 

  113. Muto G, Kotani H, Kondo T, Morita R, Tsuruta S, Kobayashi T, Luche H, Fehling HJ, Walsh M, Choi Y et al (2013) TRAF6 is essential for maintenance of regulatory T cells that suppress Th2 type autoimmunity. PLoS One 8:e74639

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Cejas PJ, Walsh MC, Pearce EL, Han D, Harms GM, Artis D, Turka LA, Choi Y (2010) TRAF6 inhibits Th17 differentiation and TGF-beta-mediated suppression of IL-2. Blood 115:4750–4757

    CAS  PubMed Central  PubMed  Google Scholar 

  115. van Loosdregt J, Fleskens V, Fu J, Brenkman AB, Bekker CP, Pals CE, Meerding J, Berkers CR, Barbi J, Grone A et al (2013) Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39:259–271

    PubMed  Google Scholar 

  116. Chen Z, Barbi J, Bu S, Yang HY, Li Z, Gao Y, Jinasena D, Fu J, Lin F, Chen C et al (2013) The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39:272–285

    CAS  PubMed  Google Scholar 

  117. Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin LY, Patterson C (1999) Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol 19:4535–4545

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Li X, Huang M, Zheng H, Wang Y, Ren F, Shang Y, Zhai Y, Irwin DM, Shi Y, Chen D et al (2008) CHIP promotes Runx2 degradation and negatively regulates osteoblast differentiation. J Cell Biol 181:959–972

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Wang S, Li Y, Hu YH, Song R, Gao Y, Liu HY, Shu HB, Liu Y (2013) STUB1 is essential for T-cell activation by ubiquitinating CARMA1. Eur J Immunol 43:1034–1041

    CAS  PubMed  Google Scholar 

  120. Nyirenda MH, Sanvito L, Darlington PJ, O’Brien K, Zhang GX, Constantinescu CS, Bar-Or A, Gran B (2011) TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol 187:2278–2290

    CAS  PubMed  Google Scholar 

  121. Sutmuller RP, den Brok MH, Kramer M, Bennink EJ, Toonen LW, Kullberg BJ, Joosten LA, Akira S, Netea MG, Adema GJ (2006) Toll-like receptor 2 controls expansion and function of regulatory T cells. J Clin Invest 116:485–494

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Liu H, Komai-Koma M, Xu D, Liew FY (2006) Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci U S A 103:7048–7053

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Yang Y, Huang CT, Huang X, Pardoll DM (2004) Persistent Toll-like receptor signals are required for reversal of regulatory T cell-mediated CD8 tolerance. Nat Immunol 5:508–515

    CAS  PubMed  Google Scholar 

  124. Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309:1380–1384

    CAS  PubMed  Google Scholar 

  125. Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4 + CD25+ T cell-mediated suppression by dendritic cells. Science 299:1033–1036

    CAS  PubMed  Google Scholar 

  126. Chen L, Wang T, Zhou P, Ma L, Yin D, Shen J, Molinero L, Nozaki T, Phillips T, Uematsu S et al (2006) TLR engagement prevents transplantation tolerance. Am J Transplant 6:2282–2291

    CAS  PubMed  Google Scholar 

  127. LaRosa DF, Gelman AE, Rahman AH, Zhang J, Turka LA, Walsh PT (2007) CpG DNA inhibits CD4 + CD25+ Treg suppression through direct MyD88-dependent costimulation of effector CD4+ T cells. Immunol Lett 108:183–188

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Zhang N, Kruger B, Lal G, Luan Y, Yadav A, Zang W, Grimm M, Waaga-Gasser AM, Murphy B, Bromberg JS et al (2010) Inhibition of TLR4 signaling prolongs Treg-dependent murine islet allograft survival. Immunol Lett 127:119–125

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Wu H, Noordmans GA, O’Brien MR, Ma J, Zhao CY, Zhang GY, Kwan TK, Alexander SI, Chadban SJ (2012) Absence of MyD88 signaling induces donor-specific kidney allograft tolerance. J Am Soc Nephrol 23:1701–1716

    CAS  PubMed Central  PubMed  Google Scholar 

  130. Gaddis DE, Michalek SM, Katz J (2011) TLR4 signaling via MyD88 and TRIF differentially shape the CD4+ T cell response to Porphyromonas gingivalis hemagglutinin B. J Immunol 186:5772–5783

    CAS  PubMed  Google Scholar 

  131. Oberg HH, Ly TT, Ussat S, Meyer T, Kabelitz D, Wesch D (2010) Differential but direct abolishment of human regulatory T cell suppressive capacity by various TLR2 ligands. J Immunol 184:4733–4740

    CAS  PubMed  Google Scholar 

  132. Yamazaki S, Okada K, Maruyama A, Matsumoto M, Yagita H, Seya T (2011) TLR2-dependent induction of IL-10 and Foxp3+ CD25+ CD4+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo. PLoS One 6:e18833

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Chen Q, Davidson TS, Huter EN, Shevach EM (2009) Engagement of TLR2 does not reverse the suppressor function of mouse regulatory T cells, but promotes their survival. J Immunol 183:4458–4466

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Filippi CM, Ehrhardt K, Estes EA, Larsson P, Oldham JE, von Herrath MG (2011) TLR2 signaling improves immunoregulation to prevent type 1 diabetes. Eur J Immunol 41:1399–1409

    CAS  PubMed Central  PubMed  Google Scholar 

  135. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK, Bernards R (2005) A genomic and functional inventory of deubiquitinating enzymes. Cell 123:773–786

    CAS  PubMed  Google Scholar 

  136. Liu X, Li H, Zhong B, Blonska M, Gorjestani S, Yan M, Tian Q, Zhang DE, Lin X, Dong C (2013) USP18 inhibits NF-kappaB and NFAT activation during Th17 differentiation by deubiquitinating the TAK1-TAB1 complex. J Exp Med 210:1575–1590

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164

    CAS  PubMed  Google Scholar 

  138. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L et al (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381

    CAS  PubMed  Google Scholar 

  139. Quintana FJ, Jin H, Burns EJ, Nadeau M, Yeste A, Kumar D, Rangachari M, Zhu C, Xiao S, Seavitt J et al (2012) Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat Immunol 13:770–777

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Zhao Y, Thornton AM, Kinney MC, Ma CA, Spinner JJ, Fuss IJ, Shevach EM, Jain A (2011) The deubiquitinase CYLD targets Smad7 protein to regulate transforming growth factor beta (TGF-beta) signaling and the development of regulatory T cells. J Biol Chem 286:40520–40530

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Lim JH, Jono H, Komatsu K, Woo CH, Lee J, Miyata M, Matsuno T, Xu X, Huang Y, Zhang W et al (2012) CYLD negatively regulates transforming growth factor-beta-signalling via deubiquitinating Akt. Nat Commun 3:771

    PubMed Central  PubMed  Google Scholar 

  142. Reissig S, Hovelmeyer N, Weigmann B, Nikolaev A, Kalt B, Wunderlich TF, Hahn M, Neurath MF, Waisman A (2012) The tumor suppressor CYLD controls the function of murine regulatory T cells. J Immunol 189:4770–4776

    CAS  PubMed  Google Scholar 

  143. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564

    CAS  PubMed  Google Scholar 

  144. Thuille N, Wachowicz K, Hermann-Kleiter N, Kaminski S, Fresser F, Lutz-Nicoladoni C, Leitges M, Thome M, Massoumi R, Baier G (2013) PKCtheta/beta and CYLD are antagonistic partners in the NFkappaB and NFAT transactivation pathways in primary mouse CD3+ T lymphocytes. PLoS One 8:e53709

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Wohlfert EA, Grainger JR, Bouladoux N, Konkel JE, Oldenhove G, Ribeiro CH, Hall JA, Yagi R, Naik S, Bhairavabhotla R et al (2011) GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest 121:4503–4515

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Wang Y, Su MA, Wan YY (2011) An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35:337–348

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Zhang J, Chen C, Hou X, Gao Y, Lin F, Yang J, Gao Z, Pan L, Tao L, Wen C et al (2013) Identification of the E3 deubiquitinase ubiquitin-specific peptidase 21 (USP21) as a positive regulator of the transcription factor GATA3. J Biol Chem 288:9373–9382

    CAS  PubMed Central  PubMed  Google Scholar 

  148. van Loosdregt J, Brunen D, Fleskens V, Pals CE, Lam EW, Coffer PJ (2011) Rapid temporal control of Foxp3 protein degradation by sirtuin-1. PLoS One 6:e19047

    PubMed Central  PubMed  Google Scholar 

  149. Morawski PA, Mehra P, Chen C, Bhatti T, Wells AD (2013) Foxp3 protein stability is regulated by cyclin-dependent kinase 2. J Biol Chem 288:24494–24502

    CAS  PubMed  Google Scholar 

  150. Kwon HS, Lim HW, Wu J, Schnolzer M, Verdin E, Ott M (2012) Three novel acetylation sites in the Foxp3 transcription factor regulate the suppressive activity of regulatory T cells. J Immunol 188:2712–2721

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The Authors declare no financial conflicts of interest. Funding support comes from grants from the Melanoma Research Alliance, the National Institutes of Health (RO1AI099300 and RO1AI089830), “Kelly’s Dream” Foundation, the Janey Fund, and the Seraph Foundation, and gifts from Bill and Betty Topecer and Dorothy Needle. FP is a Stewart Trust Scholar, JB is supported by a Crohn’s and Colitis Foundation of America Research Fellowship.

Author information

Authors and Affiliations

  1. Immunology and Hematopoiesis Division, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    Fan Pan & Joseph Barbi

Authors
  1. Fan Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph Barbi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fan Pan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pan, F., Barbi, J. Ubiquitous points of control over regulatory T cells. J Mol Med 92, 555–569 (2014). https://doi.org/10.1007/s00109-014-1156-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-014-1156-z

Keywords

Search

Navigation