Cellular and Molecular Life Sciences

, Volume 69, Issue 12, pp 1997–2008 | Cite as

The battle against immunopathology: infectious tolerance mediated by regulatory T cells

  • David M. Gravano
  • Dario A. A. VignaliEmail author


Infectious tolerance is a process whereby one regulatory lymphoid population confers suppressive capacity on another. Diverse immune responses are induced following infection or inflammatory insult that can protect the host, or potentially cause damage if not properly controlled. Thus, the process of infectious tolerance may be critical in vivo for exerting effective immune control and maintaining immune homeostasis by generating specialized regulatory sub-populations with distinct mechanistic capabilities. Foxp3+ regulatory T cells (Tregs) are a central mediator of infectious tolerance through their ability to convert conventional T cells into induced regulatory T cells (iTregs) directly by secretion of the suppressive cytokines TGF-β, IL-10, or IL-35, or indirectly via dendritic cells. In this review, we will discuss the mechanisms and cell populations that mediate and contribute to infectious tolerance, with a focus on the intestinal environment, where tolerance induction to foreign material is critical.


Infectious tolerance Regulatory T cell Intestine Helminth Microbiota 



Dendritic cells


Experimental autoimmune encephalomyelitis


Excretory/secretory products


Indoleamine 2,3-dioxygenase


Immunodysregulation polyendocrinopathy enteropathy X-linked


Induced Tregs


Polysaccharide A


Retinoic acid


Soluble egg antigen


Regulatory T cells



Supported by the National Institutes of Health (AI39480, AI091977), St Jude NCI Comprehensive Cancer Center (CA-21765), and the American Lebanese Syrian Associated Charities.


  1. 1.
    Bluestone JA, Auchincloss H, Nepom GT, Rotrosen D, St Clair EW, Turka LA (2010) The immune tolerance network at 10 years: tolerance research at the bedside. Nat Rev Immunol 10(11):797–803. doi: 10.1038/nri2869 PubMedCrossRefGoogle Scholar
  2. 2.
    Weiner HL, da Cunha AP, Quintana F, Wu H (2011) Oral tolerance. Immunol Rev 241(1):241–259. doi: 10.1111/j.1600-065X.2011.01017.x PubMedCrossRefGoogle Scholar
  3. 3.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704. doi: 10.1146/annurev.immunol.26.021607.090331 PubMedCrossRefGoogle Scholar
  4. 4.
    Gershon RK, Kondo K (1971) Infectious immunological tolerance. Immunology 21(6):903–914PubMedGoogle Scholar
  5. 5.
    Waldmann H, Adams E, Fairchild P, Cobbold S (2006) Infectious tolerance and the long-term acceptance of transplanted tissue. Immunol Rev 212:301–313. doi: 10.1111/j.0105-2896.2006.00406.x PubMedCrossRefGoogle Scholar
  6. 6.
    Maloy KJ, Powrie F (2011) Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474(7351):298–306. doi: 10.1038/nature10208 PubMedCrossRefGoogle Scholar
  7. 7.
    Billingham RE, Brent L, Medawar PB (1953) Actively acquired tolerance of foreign cells. Nature 172(4379):603–606PubMedCrossRefGoogle Scholar
  8. 8.
    Green DR, Flood PM, Gershon RK (1983) Immunoregulatory T-cell pathways. Annu Rev Immunol 1:439–463. doi: 10.1146/annurev.iy.01.040183.002255 PubMedCrossRefGoogle Scholar
  9. 9.
    Green DR, Gershon RK, Eardley DD (1981) Functional deletion of different Ly-1 T-cell-inducer subset activities by Ly-2 suppressor T lymphocytes. Proc Natl Acad Sci USA 78(6):3819–3823PubMedCrossRefGoogle Scholar
  10. 10.
    Bursuker I, North RJ (1984) Generation and decay of the immune response to a progressive fibrosarcoma. II. Failure to demonstrate postexcision immunity after the onset of T cell-mediated suppression of immunity. J Exp Med 159(5):1312–1321Google Scholar
  11. 11.
    North RJ, Bursuker I (1984) T cell-mediated suppression of the concomitant antitumor immune response as an example of transplantation tolerance. Transpl Proc 16(2):463–469Google Scholar
  12. 12.
    Benjamin RJ, Waldmann H (1986) Induction of tolerance by monoclonal antibody therapy. Nature 320(6061):449–451. doi: 10.1038/320449a0 PubMedCrossRefGoogle Scholar
  13. 13.
    Honey K, Cobbold SP, Waldmann H (1999) CD40 ligand blockade induces CD4+ T cell tolerance and linked suppression. J Immunol 163(9):4805–4810PubMedGoogle Scholar
  14. 14.
    Graca L, Honey K, Adams E, Cobbold SP, Waldmann H (2000) Cutting edge: anti-CD154 therapeutic antibodies induce infectious transplantation tolerance. J Immunol 165(9):4783–4786PubMedGoogle Scholar
  15. 15.
    Scully R, Qin S, Cobbold S, Waldmann H (1994) Mechanisms in CD4 antibody-mediated transplantation tolerance: kinetics of induction, antigen dependency and role of regulatory T cells. Eur J Immunol 24(10):2383–2392. doi: 10.1002/eji.1830241019 PubMedCrossRefGoogle Scholar
  16. 16.
    Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J, Waldmann H (1993) “Infectious” transplantation tolerance. Science 259(5097):974–977PubMedCrossRefGoogle Scholar
  17. 17.
    Davies JD, Leong LY, Mellor A, Cobbold SP, Waldmann H (1996) T cell suppression in transplantation tolerance through linked recognition. J Immunol 156(10):3602–3607PubMedGoogle Scholar
  18. 18.
    Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M, Kuniyasu Y, Nomura T, Toda M, Takahashi T (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32PubMedCrossRefGoogle Scholar
  19. 19.
    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(3):1151–1164Google Scholar
  20. 20.
    Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27(1):68–73. doi: 10.1038/83784 PubMedCrossRefGoogle Scholar
  21. 21.
    Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21. doi: 10.1038/83713 PubMedCrossRefGoogle Scholar
  22. 22.
    Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27(1):18–20. doi: 10.1038/83707 PubMedCrossRefGoogle Scholar
  23. 23.
    Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106(12):R75–R81. doi: 10.1172/JCI11679 PubMedCrossRefGoogle Scholar
  24. 24.
    Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4(4):330–336. doi: 10.1038/ni904 PubMedCrossRefGoogle Scholar
  25. 25.
    Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061. doi: 10.1126/science.1079490 PubMedCrossRefGoogle Scholar
  26. 26.
    Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, Waldmann H (2004) Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol 172(10):6003–6010PubMedGoogle Scholar
  27. 27.
    Cobbold SP, Adams E, Graca L, Daley S, Yates S, Paterson A, Robertson NJ, Nolan KF, Fairchild PJ, Waldmann H (2006) Immune privilege induced by regulatory T cells in transplantation tolerance. Immunol Rev 213:239–255. doi: 10.1111/j.1600-065X.2006.00428.x PubMedCrossRefGoogle Scholar
  28. 28.
    Kendal AR, Chen Y, Regateiro FS, Ma J, Adams E, Cobbold SP, Hori S, Waldmann H (2011) Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance. J Exp Med. doi:10.1084/jem.20110767
  29. 29.
    Regateiro FS, Howie D, Cobbold SP, Waldmann H (2011) TGF-beta in transplantation tolerance. Curr Opin Immunol. doi: 10.1016/j.coi.2011.07.003
  30. 30.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359(6397):693–699. doi: 10.1038/359693a0 PubMedCrossRefGoogle Scholar
  31. 31.
    Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886. doi: 10.1084/jem.20030152 PubMedCrossRefGoogle Scholar
  32. 32.
    Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA (2004) Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol 172(9):5213–5221PubMedGoogle Scholar
  33. 33.
    Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W (2008) A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9(6):632–640. doi: 10.1038/ni.1607 PubMedCrossRefGoogle Scholar
  34. 34.
    Tran DQ, Andersson J, Hardwick D, Bebris L, Illei GG, Shevach EM (2009) Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures. Blood 113(21):5125–5133. doi: 10.1182/blood-2009-01-199950 PubMedCrossRefGoogle Scholar
  35. 35.
    Shevach EM (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30(5):636–645. doi: 10.1016/j.immuni.2009.04.010 PubMedCrossRefGoogle Scholar
  36. 36.
    Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O’Shea JJ, Shevach EM (2008) CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med 205(9):1975–1981. doi: 10.1084/jem.20080308 PubMedCrossRefGoogle Scholar
  37. 37.
    Jonuleit H, Schmitt E, Kakirman H, Stassen M, Knop J, Enk AH (2002) Infectious tolerance: human CD25(+) regulatory T cells convey suppressor activity to conventional CD4(+) T helper cells. J Exp Med 196(2):255–260PubMedCrossRefGoogle Scholar
  38. 38.
    Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389(6652):737–742. doi: 10.1038/39614 PubMedCrossRefGoogle Scholar
  39. 39.
    Roncarolo MG, Gregori S, Battaglia M, Bacchetta R, Fleischhauer K, Levings MK (2006) Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 212:28–50. doi: 10.1111/j.0105-2896.2006.00420.x PubMedCrossRefGoogle Scholar
  40. 40.
    Stassen M, Fondel S, Bopp T, Richter C, Muller C, Kubach J, Becker C, Knop J, Enk AH, Schmitt S, Schmitt E, Jonuleit H (2004) Human CD25+ regulatory T cells: two subsets defined by the integrins alpha 4 beta 7 or alpha 4 beta 1 confer distinct suppressive properties upon CD4+ T helper cells. Eur J Immunol 34(5):1303–1311. doi: 10.1002/eji.200324656 PubMedCrossRefGoogle Scholar
  41. 41.
    Dieckmann D, Bruett CH, Ploettner H, Lutz MB, Schuler G (2002) Human CD4(+)CD25(+) regulatory, contact-dependent T cells induce interleukin 10-producing, contact-independent type 1-like regulatory T cells [corrected]. J Exp Med 196(2):247–253PubMedCrossRefGoogle Scholar
  42. 42.
    Mekala DJ, Alli RS, Geiger TL (2005) IL-10-dependent infectious tolerance after the treatment of experimental allergic encephalomyelitis with redirected CD4+CD25+ T lymphocytes. Proc Natl Acad Sci USA 102(33):11817–11822. doi: 10.1073/pnas.0505445102 PubMedCrossRefGoogle Scholar
  43. 43.
    Selvaraj RK, Geiger TL (2008) Mitigation of experimental allergic encephalomyelitis by TGF-beta induced Foxp3+ regulatory T lymphocytes through the induction of anergy and infectious tolerance. J Immunol 180(5):2830–2838PubMedGoogle Scholar
  44. 44.
    Maynard CL, Harrington LE, Janowski KM, Oliver JR, Zindl CL, Rudensky AY, Weaver CT (2007) Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. Nat Immunol 8(9):931–941. doi: 10.1038/ni1504 PubMedCrossRefGoogle Scholar
  45. 45.
    Chaudhry A, Samstein RM, Treuting P, Liang Y, Pils MC, Heinrich JM, Jack RS, Wunderlich FT, Bruning JC, Muller W, Rudensky AY (2011) Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34(4):566–578. doi: 10.1016/j.immuni.2011.03.018 PubMedCrossRefGoogle Scholar
  46. 46.
    Huber S, Gagliani N, Esplugues E, O’Connor W Jr, Huber FJ, Chaudhry A, Kamanaka M, Kobayashi Y, Booth CJ, Rudensky AY, Roncarolo MG, Battaglia M, Flavell RA (2011) Th17 cells express interleukin-10 receptor and are controlled by Foxp3 and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34(4):554–565. doi: 10.1016/j.immuni.2011.01.020 PubMedCrossRefGoogle Scholar
  47. 47.
    Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, Treuting P, Siewe L, Roers A, Henderson WR Jr, Muller W, Rudensky AY (2008) Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28(4):546–558. doi: 10.1016/j.immuni.2008.02.017 PubMedCrossRefGoogle Scholar
  48. 48.
    Esplugues E, Huber S, Gagliani N, Hauser AE, Town T, Wan YY, O’Connor W Jr, Rongvaux A, Van Rooijen N, Haberman AM, Iwakura Y, Kuchroo VK, Kolls JK, Bluestone JA, Herold KC, Flavell RA (2011) Control of TH17 cells occurs in the small intestine. Nature 475(7357):514–518. doi: 10.1038/nature10228 PubMedCrossRefGoogle Scholar
  49. 49.
    Collison LW, Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, Finkelstein D, Forbes K, Workman CJ, Brown SA, Rehg JE, Jones ML, Ni HT, Artis D, Turk MJ, Vignali DA (2010) IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 11(12):1093–1101. doi: 10.1038/ni.1952 PubMedCrossRefGoogle Scholar
  50. 50.
    Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Blumberg RS, Vignali DA (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566–569. doi: 10.1038/nature06306 PubMedCrossRefGoogle Scholar
  51. 51.
    Chaturvedi V, Collison LW, Guy CS, Workman CJ, Vignali DA (2011) Cutting edge: human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. J Immunol 186(12):6661–6666. doi: 10.4049/jimmunol.1100315 PubMedCrossRefGoogle Scholar
  52. 52.
    Cobbold SP, Adams E, Nolan KF, Regateiro FS, Waldmann H (2010) Connecting the mechanisms of T-cell regulation: dendritic cells as the missing link. Immunol Rev 236:203–218. doi: 10.1111/j.1600-065X.2010.00913.x PubMedCrossRefGoogle Scholar
  53. 53.
    Yamazaki S, Bonito AJ, Spisek R, Dhodapkar M, Inaba K, Steinman RM (2007) Dendritic cells are specialized accessory cells along with TGF- for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors. Blood 110(13):4293–4302. doi: 10.1182/blood-2007-05-088831 PubMedCrossRefGoogle Scholar
  54. 54.
    Wang L, Pino-Lagos K, de Vries VC, Guleria I, Sayegh MH, Noelle RJ (2008) Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc Natl Acad Sci USA 105(27):9331–9336. doi: 10.1073/pnas.0710441105 PubMedCrossRefGoogle Scholar
  55. 55.
    Martin P, Del Hoyo GM, Anjuere F, Arias CF, Vargas HH, Fernandez LA, Parrillas V, Ardavin C (2002) Characterization of a new subpopulation of mouse CD8alpha+ B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential. Blood 100(2):383–390PubMedCrossRefGoogle Scholar
  56. 56.
    Hadeiba H, Sato T, Habtezion A, Oderup C, Pan J, Butcher EC (2008) CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol 9(11):1253–1260. doi: 10.1038/ni.1658 PubMedCrossRefGoogle Scholar
  57. 57.
    Farquhar CA, Paterson AM, Cobbold SP, Garcia Rueda H, Fairchild PJ, Yates SF, Adams E, Saunders NJ, Waldmann H, Nolan KF (2010) Tolerogenicity is not an absolute property of a dendritic cell. Eur J Immunol 40(6):1728–1737. doi: 10.1002/eji.200939974 PubMedCrossRefGoogle Scholar
  58. 58.
    Yates SF, Paterson AM, Nolan KF, Cobbold SP, Saunders NJ, Waldmann H, Fairchild PJ (2007) Induction of regulatory T cells and dominant tolerance by dendritic cells incapable of full activation. J Immunol 179(2):967–976PubMedGoogle Scholar
  59. 59.
    Gregori S, Tomasoni D, Pacciani V, Scirpoli M, Battaglia M, Magnani CF, Hauben E, Roncarolo MG (2010) Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood 116(6):935–944. doi: 10.1182/blood-2009-07-234872 PubMedCrossRefGoogle Scholar
  60. 60.
    Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG (2005) Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+CD4+ Tr cells. Blood 105(3):1162–1169. doi: 10.1182/blood-2004-03-1211 PubMedCrossRefGoogle Scholar
  61. 61.
    Kirchberger S, Majdic O, Steinberger P, Bluml S, Pfistershammer K, Zlabinger G, Deszcz L, Kuechler E, Knapp W, Stockl J (2005) Human rhinoviruses inhibit the accessory function of dendritic cells by inducing sialoadhesin and B7–H1 expression. J Immunol 175(2):1145–1152PubMedGoogle Scholar
  62. 62.
    Seyerl M, Kirchberger S, Majdic O, Seipelt J, Jindra C, Schrauf C, Stockl J (2010) Human rhinoviruses induce IL-35-producing Treg via induction of B7–H1 (CD274) and sialoadhesin (CD169) on DC. Eur J Immunol 40(2):321–329. doi: 10.1002/eji.200939527 PubMedCrossRefGoogle Scholar
  63. 63.
    Chappert P, Schwartz RH (2010) Induction of T cell anergy: integration of environmental cues and infectious tolerance. Curr Opin Immunol 22(5):552–559. doi: 10.1016/j.coi.2010.08.005 PubMedCrossRefGoogle Scholar
  64. 64.
    Morelli AE, Thomson AW (2007) Tolerogenic dendritic cells and the quest for transplant tolerance. Nat Rev Immunol 7(8):610–621. doi: 10.1038/nri2132 PubMedCrossRefGoogle Scholar
  65. 65.
    Hilkens CM, Isaacs JD, Thomson AW (2010) Development of dendritic cell-based immunotherapy for autoimmunity. Int Rev Immunol 29(2):156–183. doi: 10.3109/08830180903281193 PubMedCrossRefGoogle Scholar
  66. 66.
    Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334. doi: 10.1146/annurev.immunol.21.120601.141110 PubMedCrossRefGoogle Scholar
  67. 67.
    Wells AD (2009) New insights into the molecular basis of T cell anergy: anergy factors, avoidance sensors, and epigenetic imprinting. J Immunol 182(12):7331–7341. doi: 10.4049/jimmunol.0803917 PubMedCrossRefGoogle Scholar
  68. 68.
    Powell JD, Lerner CG, Schwartz RH (1999) Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol 162(5):2775–2784PubMedGoogle Scholar
  69. 69.
    Zheng Y, Collins SL, Lutz MA, Allen AN, Kole TP, Zarek PE, Powell JD (2007) A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol 178(4):2163–2170 pii: 178/4/2163PubMedGoogle Scholar
  70. 70.
    Thomson AW, Turnquist HR, Raimondi G (2009) Immunoregulatory functions of mTOR inhibition. Nat Rev Immunol 9(5):324–337. doi: 10.1038/nri2546 PubMedCrossRefGoogle Scholar
  71. 71.
    Hardie DG (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Natl Rev Mol Cell Biol 8(10):774–785. doi: 10.1038/nrm2249 CrossRefGoogle Scholar
  72. 72.
    Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30(6):832–844. doi: 10.1016/j.immuni.2009.04.014 PubMedCrossRefGoogle Scholar
  73. 73.
    Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2, 3-dioxygenase. Immunity 22(5):633–642. doi: 10.1016/j.immuni.2005.03.013 PubMedCrossRefGoogle Scholar
  74. 74.
    Grallert B, Boye E (2007) The Gcn2 kinase as a cell cycle regulator. Cell Cycle 6(22):2768–2772PubMedCrossRefGoogle Scholar
  75. 75.
    Zarek PE, Powell JD (2007) Adenosine and anergy. Autoimmunity 40(6):425–432. doi: 10.1080/08916930701464939 PubMedCrossRefGoogle Scholar
  76. 76.
    Zarek PE, Huang CT, Lutz ER, Kowalski J, Horton MR, Linden J, Drake CG, Powell JD (2008) A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells. Blood 111(1):251–259. doi: 10.1182/blood-2007-03-081646 PubMedCrossRefGoogle Scholar
  77. 77.
    Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, Lafaille JJ, Dustin ML (2006) Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med 203(3):505–511. doi: 10.1084/jem.20050783 PubMedCrossRefGoogle Scholar
  78. 78.
    Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA (2006) Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7(1):83–92. doi: 10.1038/ni1289 PubMedCrossRefGoogle Scholar
  79. 79.
    Misra N, Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV (2004) Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol 172(8):4676–4680PubMedGoogle Scholar
  80. 80.
    Serra P, Amrani A, Yamanouchi J, Han B, Thiessen S, Utsugi T, Verdaguer J, Santamaria P (2003) CD40 ligation releases immature dendritic cells from the control of regulatory CD4+CD25+ T cells. Immunity 19(6):877–889PubMedCrossRefGoogle Scholar
  81. 81.
    Onishi Y, Fehervari Z, Yamaguchi T, Sakaguchi S (2008) Foxp3+ natural regulatory T cells preferentially form aggregates on dendritic cells in vitro and actively inhibit their maturation. Proc Natl Acad Sci USA 105(29):10113–10118. doi: 10.1073/pnas.0711106105 PubMedCrossRefGoogle Scholar
  82. 82.
    Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, Nomura T, Sakaguchi S (2008) CTLA-4 control over Foxp3+ regulatory T cell function. Science 322(5899):271–275. doi: 10.1126/science.1160062 PubMedCrossRefGoogle Scholar
  83. 83.
    Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332(6029):600–603. doi: 10.1126/science.1202947 PubMedCrossRefGoogle Scholar
  84. 84.
    Workman CJ, Cauley LS, Kim IJ, Blackman MA, Woodland DL, Vignali DA (2004) Lymphocyte activation gene-3 (CD223) regulates the size of the expanding T cell population following antigen activation in vivo. J Immunol 172(9):5450–5455PubMedGoogle Scholar
  85. 85.
    Workman CJ, Vignali DA (2005) Negative regulation of T cell homeostasis by lymphocyte activation gene-3 (CD223). J Immunol 174(2):688–695PubMedGoogle Scholar
  86. 86.
    Huang CT, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, Hipkiss EL, Ravi S, Kowalski J, Levitsky HI, Powell JD, Pardoll DM, Drake CG, Vignali DA (2004) Role of LAG-3 in regulatory T cells. Immunity 21(4):503–513. doi: 10.1016/j.immuni.2004.08.010 PubMedCrossRefGoogle Scholar
  87. 87.
    Liang B, Workman C, Lee J, Chew C, Dale BM, Colonna L, Flores M, Li N, Schweighoffer E, Greenberg S, Tybulewicz V, Vignali D, Clynes R (2008) Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 180(9):5916–5926PubMedGoogle Scholar
  88. 88.
    Onodera T, Jang MH, Guo Z, Yamasaki M, Hirata T, Bai Z, Tsuji NM, Nagakubo D, Yoshie O, Sakaguchi S, Takikawa O, Miyasaka M (2009) Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes: functional involvement of the CTLA-4/B7 and CCL22/CCR4 interactions. J Immunol 183(9):5608–5614. doi: 10.4049/jimmunol.0804116 PubMedCrossRefGoogle Scholar
  89. 89.
    Mellor AL, Chandler P, Baban B, Hansen AM, Marshall B, Pihkala J, Waldmann H, Cobbold S, Adams E, Munn DH (2004) Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2, 3 dioxygenase. Int Immunol 16(10):1391–1401. doi: 10.1093/intimm/dxh140 PubMedCrossRefGoogle Scholar
  90. 90.
    Baban B, Chandler PR, Johnson BA 3rd, Huang L, Li M, Sharpe ML, Francisco LM, Sharpe AH, Blazar BR, Munn DH, Mellor AL (2011) Physiologic control of IDO competence in splenic dendritic cells. J Immunol 187(5):2329–2335. doi: 10.4049/jimmunol.1100276 PubMedCrossRefGoogle Scholar
  91. 91.
    Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, Fairchild PJ, Mellor AL, Ron D, Waldmann H (2009) Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci USA 106(29):12055–12060. doi: 10.1073/pnas.0903919106 PubMedCrossRefGoogle Scholar
  92. 92.
    Pallotta MT, Orabona C, Volpi C, Vacca C, Belladonna ML, Bianchi R, Servillo G, Brunacci C, Calvitti M, Bicciato S, Mazza EM, Boon L, Grassi F, Fioretti MC, Fallarino F, Puccetti P, Grohmann U (2011) Indoleamine 2, 3-dioxygenase is a signaling protein in long-term tolerance by dendritic cells. Nat Immunol 12(9):870–878. doi: 10.1038/ni.2077 PubMedCrossRefGoogle Scholar
  93. 93.
    Izcue A, Coombes JL, Powrie F (2009) Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 27:313–338. doi: 10.1146/annurev.immunol.021908.132657 PubMedCrossRefGoogle Scholar
  94. 94.
    Grainger JR, Hall JA, Bouladoux N, Oldenhove G, Belkaid Y (2010) Microbe-dendritic cell dialog controls regulatory T-cell fate. Immunol Rev 234(1):305–316. doi: 10.1111/j.0105-2896.2009.00880.x PubMedCrossRefGoogle Scholar
  95. 95.
    Iwasaki A, Kelsall BL (1999) Freshly isolated Peyer’s patch, but not spleen, dendritic cells produce interleukin 10 and induce the differentiation of T helper type 2 cells. J Exp Med 190(2):229–239PubMedCrossRefGoogle Scholar
  96. 96.
    Chirdo FG, Millington OR, Beacock-Sharp H, Mowat AM (2005) Immunomodulatory dendritic cells in intestinal lamina propria. Eur J Immunol 35(6):1831–1840. doi: 10.1002/eji.200425882 PubMedCrossRefGoogle Scholar
  97. 97.
    Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204(8):1775–1785. doi: 10.1084/jem.20070602 PubMedCrossRefGoogle Scholar
  98. 98.
    Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204(8):1757–1764. doi: 10.1084/jem.20070590 PubMedCrossRefGoogle Scholar
  99. 99.
    Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X, Reichardt LF, Bluestone JA, Sheppard D (2007) Loss of integrin alpha(v)beta8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449(7160):361–365. doi: 10.1038/nature06110 PubMedCrossRefGoogle Scholar
  100. 100.
    Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ (2007) All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 204(8):1765–1774. doi: 10.1084/jem.20070719 PubMedCrossRefGoogle Scholar
  101. 101.
    Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317(5835):256–260. doi: 10.1126/science.1145697 PubMedCrossRefGoogle Scholar
  102. 102.
    Mucida D, Pino-Lagos K, Kim G, Nowak E, Benson MJ, Kronenberg M, Noelle RJ, Cheroutre H (2009) Retinoic acid can directly promote TGF-beta-mediated Foxp3(+) Treg cell conversion of naive T cells. Immunity 30(4):471–472. doi: 10.1016/j.immuni.2009.03.008. Author reply 472–473Google Scholar
  103. 103.
    Hill JA, Hall JA, Sun CM, Cai Q, Ghyselinck N, Chambon P, Belkaid Y, Mathis D, Benoist C (2008) Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 29(5):758–770. doi: 10.1016/j.immuni.2008.09.018 PubMedCrossRefGoogle Scholar
  104. 104.
    Okada H, Kuhn C, Feillet H, Bach JF (2010) The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol 160(1):1–9. doi: 10.1111/j.1365-2249.2010.04139.x PubMedCrossRefGoogle Scholar
  105. 105.
    Lee YK, Mazmanian SK (2010) Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330(6012):1768–1773. doi: 10.1126/science.1195568 PubMedCrossRefGoogle Scholar
  106. 106.
    Macpherson AJ, Harris NL (2004) Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 4(6):478–485. doi: 10.1038/nri1373 PubMedCrossRefGoogle Scholar
  107. 107.
    Round JL, Mazmanian SK (2010) Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA 107(27):12204–12209. doi: 10.1073/pnas.0909122107 PubMedCrossRefGoogle Scholar
  108. 108.
    Atarashi K, Tanoue T, Shima T, Imaoka A, Kuwahara T, Momose Y, Cheng G, Yamasaki S, Saito T, Ohba Y, Taniguchi T, Takeda K, Hori S, Ivanov II, Umesaki Y, Itoh K, Honda K (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331(6015):337–341. doi: 10.1126/science.1198469 PubMedCrossRefGoogle Scholar
  109. 109.
    Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S, McCoy KD, Macpherson AJ (2011) Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34(5):794–806. doi: 10.1016/j.immuni.2011.03.021 PubMedCrossRefGoogle Scholar
  110. 110.
    Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK (2011) The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332(6032):974–977. doi: 10.1126/science.1206095 PubMedCrossRefGoogle Scholar
  111. 111.
    Hewitson JP, Grainger JR, Maizels RM (2009) Helminth immunoregulation: the role of parasite secreted proteins in modulating host immunity. Mol Biochem Parasitol 167(1):1–11. doi: 10.1016/j.molbiopara.2009.04.008 PubMedCrossRefGoogle Scholar
  112. 112.
    Finney CA, Taylor MD, Wilson MS, Maizels RM (2007) Expansion and activation of CD4(+)CD25(+) regulatory T cells in Heligmosomoides polygyrus infection. Eur J Immunol 37(7):1874–1886. doi: 10.1002/eji.200636751 PubMedCrossRefGoogle Scholar
  113. 113.
    Rausch S, Huehn J, Kirchhoff D, Rzepecka J, Schnoeller C, Pillai S, Loddenkemper C, Scheffold A, Hamann A, Lucius R, Hartmann S (2008) Functional analysis of effector and regulatory T cells in a parasitic nematode infection. Infect Immun 76(5):1908–1919. doi: 10.1128/IAI.01233-07 PubMedCrossRefGoogle Scholar
  114. 114.
    Metwali A, Setiawan T, Blum AM, Urban J, Elliott DE, Hang L, Weinstock JV (2006) Induction of CD8+ regulatory T cells in the intestine by Heligmosomoides polygyrus infection. Am J Physiol Gastrointest Liver Physiol 291(2):G253–G259. doi: 10.1152/ajpgi.00409.2005 PubMedCrossRefGoogle Scholar
  115. 115.
    Hussaarts L, van der Vlugt LE, Yazdanbakhsh M, Smits HH (2011) Regulatory B-cell induction by helminths: implications for allergic disease. J Allergy Clin Immunol. doi: 10.1016/j.jaci.2011.05.012
  116. 116.
    McSorley HJ, Harcus YM, Murray J, Taylor MD, Maizels RM (2008) Expansion of Foxp3+ regulatory T cells in mice infected with the filarial parasite Brugia malayi. J Immunol 181(9):6456–6466PubMedGoogle Scholar
  117. 117.
    Grainger JR, Smith KA, Hewitson JP, McSorley HJ, Harcus Y, Filbey KJ, Finney CA, Greenwood EJ, Knox DP, Wilson MS, Belkaid Y, Rudensky AY, Maizels RM (2010) Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway. J Exp Med 207(11):2331–2341. doi: 10.1084/jem.20101074 PubMedCrossRefGoogle Scholar
  118. 118.
    Taylor MD, van der Werf N, Harris A, Graham AL, Bain O, Allen JE, Maizels RM (2009) Early recruitment of natural CD4+ Foxp3+ Treg cells by infective larvae determines the outcome of filarial infection. Eur J Immunol 39(1):192–206. doi: 10.1002/eji.200838727 PubMedCrossRefGoogle Scholar
  119. 119.
    Rausch S, Huehn J, Loddenkemper C, Hepworth MR, Klotz C, Sparwasser T, Hamann A, Lucius R, Hartmann S (2009) Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells. Eur J Immunol 39(11):3066–3077. doi: 10.1002/eji.200939644 PubMedCrossRefGoogle Scholar
  120. 120.
    Burton OT, Gibbs S, Miller N, Jones FM, Wen L, Dunne DW, Cooke A, Zaccone P (2010) Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens. Eur J Immunol 40(8):2221–2229. doi: 10.1002/eji.200939998 PubMedCrossRefGoogle Scholar
  121. 121.
    Zaccone P, Burton O, Miller N, Jones FM, Dunne DW, Cooke A (2009) Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice. Eur J Immunol 39(4):1098–1107. doi: 10.1002/eji.200838871 PubMedCrossRefGoogle Scholar
  122. 122.
    Segura M, Su Z, Piccirillo C, Stevenson MM (2007) Impairment of dendritic cell function by excretory-secretory products: a potential mechanism for nematode-induced immunosuppression. Eur J Immunol 37(7):1887–1904. doi: 10.1002/eji.200636553 PubMedCrossRefGoogle Scholar
  123. 123.
    Smith KA, Hochweller K, Hammerling GJ, Boon L, MacDonald AS, Maizels RM (2011) Chronic helminth infection promotes immune regulation in vivo through dominance of CD11cloCD103- dendritic cells. J Immunol 186(12):7098–7109. doi: 10.4049/jimmunol.1003636 PubMedCrossRefGoogle Scholar
  124. 124.
    Ochoa-Reparaz J, Mielcarz DW, Ditrio LE, Burroughs AR, Begum-Haque S, Dasgupta S, Kasper DL, Kasper LH (2010) Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol 185(7):4101–4108. doi: 10.4049/jimmunol.1001443 PubMedCrossRefGoogle Scholar
  125. 125.
    Saunders KA, Raine T, Cooke A, Lawrence CE (2007) Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immun 75(1):397–407. doi: 10.1128/IAI.00664-06 PubMedCrossRefGoogle Scholar
  126. 126.
    Dittrich AM, Erbacher A, Specht S, Diesner F, Krokowski M, Avagyan A, Stock P, Ahrens B, Hoffmann WH, Hoerauf A, Hamelmann E (2008) Helminth infection with Litomosoides sigmodontis induces regulatory T cells and inhibits allergic sensitization, airway inflammation, and hyperreactivity in a murine asthma model. J Immunol 180(3):1792–1799PubMedGoogle Scholar

Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  1. 1.Department of ImmunologySt. Jude Children’s Research HospitalMemphisUSA

Personalised recommendations