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Regulatory T Cell-Mediated Tissue Repair

  • Jihye Hong
  • Byung-Soo KimEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1064)

Abstract

Regulatory T-cells (Treg cells) are a specific group of T-cells that maintain immune homeostasis by counteracting the immune responses of conventional T-cells. So far, the therapeutic applications of Treg cells have focused on the treatment of autoimmune diseases, as depletion of Treg cells or Treg-related genes is known to cause autoimmune defects. However, Treg cells can be a potential solution for tissue repair as they can terminate the pro-inflammatory phase and initiate the anti-inflammatory or regenerative phase at the tissue injury site. This review summarizes the known characteristics of Treg cells and lists examples of their therapeutic applications. The use of Treg cells in the treatment of myocardial infarctions, skeletal muscle injuries, and ischemia injuries has revealed their potential as a promising tissue repair method. We have also discussed the limitations and scope of Treg cells in tissue repair.

Keywords

Inflammation Regulatory T cell Tissue repair 

References

  1. Ardon H, Verbinnen B, Maes W, Beez T, Van Gool S, De Vleeschouwer S (2010) Technical advancement in regulatory T cell isolation and characterization using CD127 expression in patients with malignant glioma treated with autologous dendritic cell vaccination. J Immunol Methods 352(1):169–173.  https://doi.org/10.1016/j.jim.2009.10.007 CrossRefPubMedGoogle Scholar
  2. Arnold L, Henry A, Poron F, Baba-Amer Y, Van Rooijen N, Plonquet A, Gherardi RK, Chazaud B (2007) Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med 204(5):1057–1069.  https://doi.org/10.1084/jem.20070075 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Arpaia N, Green JA, Moltedo B, Arvey A, Hemmers S, Yuan S, Treuting PM, Rudensky AY (2015) A distinct function of regulatory T cells in tissue protection. Cell 162(5):1078–1089.  https://doi.org/10.1016/j.cell.2015.08.021 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Asseman C, Mauze S, Leach MW, Coffman RL, Powrie F (1999) An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. J Exp Med 190(7):995–1004.  https://doi.org/10.1084/jem.190.7.995 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, Kuchroo VK, Oukka M, Weiner HL (2007) A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 8(12):1380.  https://doi.org/10.1038/ni1541 CrossRefPubMedGoogle Scholar
  6. Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, Dagna-Bricarelli F, Sartirana C, Matthes-Martin S, Lawitschka A (2006) Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest 116(6):1713.  https://doi.org/10.1172/JCI25112 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Banerjee DK, Dhodapkar MV, Matayeva E, Steinman RM, Dhodapkar KM (2006) Expansion of FOXP3 high regulatory T cells by human dendritic cells (DCs) in vitro and after injection of cytokine-matured DCs in myeloma patients. Blood 108(8):2655–2661.  https://doi.org/10.1182/blood-2006-03-011353 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 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.  https://doi.org/10.1038/ng.83713 CrossRefPubMedGoogle Scholar
  9. 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(7090):235.  https://doi.org/10.1038/nature04753 CrossRefPubMedGoogle Scholar
  10. Bonomo A, Kehn PJ, Shevach EM (1995) Post-thymectomy autoimmunity: abnormal T-cell homeostasis. Immunol Today 16(2):61–67.  https://doi.org/10.1016/0167-5699(95)80089-1 CrossRefPubMedGoogle Scholar
  11. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J, DeFor T, Levine BL, June CH, Rubinstein P (2011) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117(3):1061–1070.  https://doi.org/10.1182/blood-2010-07-293795 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, Sefik E, Tan TG, Wagers AJ, Benoist C (2013) A special population of regulatory T cells potentiates muscle repair. Cell 155(6):1282–1295.  https://doi.org/10.1016/j.cell.2013.10.054 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Bystry RS, Aluvihare V, Welch KA, Kallikourdis M, Betz AG (2001) B cells and professional APCs recruit regulatory T cells via CCL4. Nat Immunol 2(12):1126.  https://doi.org/10.1038/ni735 CrossRefPubMedGoogle Scholar
  14. Canavan JB, Afzali B, Scottà C, Fazekasova H, Edozie FC, Macdonald TT, Hernandez-Fuentes MP, Lombardi G, Lord GM (2012) A rapid diagnostic test for human regulatory T-cell function to enable regulatory T-cell therapy. Blood 119(8):e57–e66.  https://doi.org/10.1182/blood-2011-09-380048 CrossRefPubMedGoogle Scholar
  15. Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ (2007) Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27(4):635–646.  https://doi.org/10.1016/j.immuni.2007.08.014 CrossRefPubMedGoogle Scholar
  16. Chazaud B, Sonnet C, Lafuste P, Bassez G, Rimaniol A-C, Poron F, Authier F-J, Dreyfus PA, Gherardi RK (2003) Satellite cells attract monocytes and use macrophages as a support to escape apoptosis and enhance muscle growth. J Cell Biol 163(5):1133–1143.  https://doi.org/10.1083/jcb.200212046 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Chen W, Jin W, Wahl SM (1998) Engagement of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) induces transforming growth factor β (TGF-β) production by murine CD4+ T cells. J Exp Med 188(10):1849–1857.  https://doi.org/10.1084/jem.188.10.1849 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Chen W, Jin W, Hardegen N, K-j L, 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-β induction of transcription factor Foxp3. J Exp Med 198(12):1875–1886.  https://doi.org/10.1084/jem.20030152 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Choo EH, Lee J-H, Park E-H, Park HE, Jung N-C, Kim T-H, Koh Y-S, Kim E, Seung K-B, Park C (2017) Infarcted myocardium-primed dendritic cells improve remodeling and cardiac function after myocardial infarction by modulating the Treg and macrophage polarization. Circulation.  https://doi.org/10.1161/CIRCULATIONAHA.116.023106 CrossRefGoogle Scholar
  20. 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.  https://doi.org/10.1038/nature06306 CrossRefGoogle Scholar
  21. Coombes JL, Siddiqui KR, Arancibia-Cárcamo CV, Hall J, Sun C-M, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β–and retinoic acid–dependent mechanism. J Exp Med 204(8):1757–1764.  https://doi.org/10.1084/jem.20070590 CrossRefPubMedPubMedCentralGoogle Scholar
  22. D’alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, Pipeling MR, Brower RG, Tuder RM, McDyer JF (2009) CD4+ CD25+ Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest 119(10):2898.  https://doi.org/10.1172/JCI36498 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Eming SA, Krieg T, Davidson JM (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 127(3):514–525.  https://doi.org/10.1038/sj.jid.5700701 CrossRefPubMedGoogle Scholar
  24. Ertl G, Frantz S (2005) Healing after myocardial infarction. Cardiovasc Res 66(1):22–32.  https://doi.org/10.1016/j.cardiores.2005.01.011 CrossRefPubMedGoogle Scholar
  25. Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-β induces a regulatory phenotype in CD4+ CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172(9):5149–5153.  https://doi.org/10.4049/jimmunol.172.9.5149 CrossRefPubMedGoogle Scholar
  26. Faustino L, da Fonseca DM, Takenaka MC, Mirotti L, Florsheim EB, Guereschi MG, Silva JS, Basso AS, Russo M (2013) Regulatory T cells migrate to airways via CCR4 and attenuate the severity of airway allergic inflammation. J Immunol 190(6):2614–2621.  https://doi.org/10.4049/jimmunol.1202354 CrossRefPubMedGoogle Scholar
  27. 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.  https://doi.org/10.1038/ni904 CrossRefGoogle Scholar
  28. Gandolfo MT, Jang HR, Bagnasco SM, Ko G-J, Agreda P, Satpute SR, Crow MT, King LS, Rabb H (2009) Foxp3+ regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int 76(7):717–729.  https://doi.org/10.1038/ki.2009.259 CrossRefPubMedGoogle Scholar
  29. Golovina TN, Mikheeva T, Suhoski MM, Aqui NA, Tai VC, Shan X, Liu R, Balcarcel RR, Fisher N, Levine BL (2008) CD28 costimulation is essential for human T regulatory expansion and function. J Immunol 181(4):2855–2868.  https://doi.org/10.4049/jimmunol.181.4.2855 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32(5):593–604.  https://doi.org/10.1016/j.immuni.2010.05.007 CrossRefPubMedGoogle Scholar
  31. Gottschalk RA, Corse E, Allison JP (2012) Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J Immunol 188(3):976–980.  https://doi.org/10.4049/jimmunol.1102964 CrossRefPubMedGoogle Scholar
  32. Groux H, O’garra A, Bigler M, Rouleau M (1997) A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389(6652):737.  https://doi.org/10.1038/39614 CrossRefPubMedGoogle Scholar
  33. Groux H, Fournier N, Cottrez F (2004) Role of dendritic cells in the generation of regulatory T cells. Semin Immunol 16(2):99–106.  https://doi.org/10.1016/j.smim.2003.12.004 CrossRefPubMedGoogle Scholar
  34. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061.  https://doi.org/10.1126/science.1079490 CrossRefPubMedGoogle Scholar
  35. Iellem A, Mariani M, Lang R, Recalde H, Panina-Bordignon P, Sinigaglia F, D’Ambrosio D (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+ CD25+ regulatory T cells. J Exp Med 194(6):847–854.  https://doi.org/10.1084/jem.194.6.847 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Jonuleit H, Schmitt E, Schuler G, Knop J, Enk AH (2000) Induction of interleukin 10–producing, nonproliferating CD4+ T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 192(9):1213–1222.  https://doi.org/10.1084/jem.192.9.1213 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Jonuleit H, Schmitt E, Steinbrink K, Enk AH (2001) Dendritic cells as a tool to induce anergic and regulatory T cells. Trends Immunol 22(7):394–400.  https://doi.org/10.1016/S1471-4906(01)01952-4 CrossRefPubMedGoogle Scholar
  38. 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(7385):395.  https://doi.org/10.1038/nature10772 CrossRefPubMedPubMedCentralGoogle Scholar
  39. Kinsey GR, Li L, Okusa MD (2008) Inflammation in acute kidney injury. Nephron Exp Nephrol 109(4):e102–e107.  https://doi.org/10.1159/000142934 CrossRefPubMedPubMedCentralGoogle Scholar
  40. Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6(12):1219.  https://doi.org/10.1038/ni1265 CrossRefPubMedGoogle Scholar
  41. Lee I, Wang L, Wells AD, Dorf ME, Ozkaynak E, Hancock WW (2005) Recruitment of Foxp3+ T regulatory cells mediating allograft tolerance depends on the CCR4 chemokine receptor. J Exp Med 201(7):1037–1044.  https://doi.org/10.1084/jem.20041709 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Levings MK, Sangregorio R, Galbiati F, Squadrone S, de Waal Malefyt R, Roncarolo M-G (2001) IFN-α and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 166(9):5530–5539.  https://doi.org/10.4049/jimmunol.166.9.5530 CrossRefPubMedGoogle Scholar
  43. Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and-independent mechanisms. Immunity 25(3):455–471.  https://doi.org/10.1016/j.immuni.2006.07.011 CrossRefPubMedGoogle Scholar
  44. Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S, Giese T, Veltkamp R (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15(2):192–199.  https://doi.org/10.1038/nm.1927 CrossRefPubMedGoogle Scholar
  45. Lin CH, Hünig T (2003) Efficient expansion of regulatory T cells in vitro and in vivo with a CD28 superagonist. Eur J Immunol 33(3):626–638.  https://doi.org/10.1002/eji.200323570 CrossRefPubMedGoogle Scholar
  46. Liu H, Hu B, Xu D, Liew FY (2003) CD4+ CD25+ regulatory T cells cure murine colitis: the role of IL-10, TGF-β, and CTLA4. J Immunol 171(10):5012–5017.  https://doi.org/10.4049/jimmunol.171.10.5012 CrossRefPubMedGoogle Scholar
  47. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Groth BFS (2006) CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203(7):1701–1711.  https://doi.org/10.1084/jem.20060772 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Lühder F, Höglund P, Allison JP, Benoist C, Mathis D (1998) Cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med 187(3):427–432.  https://doi.org/10.1084/jem.187.3.427 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Mandapathil M, Lang S, Gorelik E, Whiteside TL (2009) Isolation of functional human regulatory T cells (Treg) from the peripheral blood based on the CD39 expression. J Immunol Methods 346(1):55–63.  https://doi.org/10.1016/j.jim.2009.05.004 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229(2):176–185.  https://doi.org/10.1002/path.4133 CrossRefPubMedGoogle Scholar
  51. Martin P, Leibovich SJ (2005) Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 15(11):599–607.  https://doi.org/10.1016/j.tcb.2005.09.002 CrossRefPubMedGoogle Scholar
  52. Martín-Gayo E, Sierra-Filardi E, Corbí AL, Toribio ML (2010) Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell development. Blood 115(26):5366–5375.  https://doi.org/10.1182/blood-2009-10-248260 CrossRefPubMedGoogle Scholar
  53. Milpied P, Renand A, Bruneau J, Mendes-Da-Cruz DA, Jacquelin S, Asnafi V, Rubio MT, MacIntyre E, Lepelletier Y, Hermine O (2009) Neuropilin-1 is not a marker of human Foxp3+ Treg. Eur J Immunol 39(6):1466–1471.  https://doi.org/10.1002/eji.200839040 CrossRefPubMedGoogle Scholar
  54. Nakamura K, Kitani A, Strober W (2001) Cell contact–dependent immunosuppression by CD4+ CD25+ regulatory T cells is mediated by cell surface–bound transforming growth factor β. J Exp Med 194(5):629–644.  https://doi.org/10.1084/jem.194.5.629 CrossRefPubMedPubMedCentralGoogle Scholar
  55. Ohnmacht C, Pullner A, King SB, Drexler I, Meier S, Brocker T, Voehringer D (2009) Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med 206(3):549–559.  https://doi.org/10.1084/jem.20082394 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Oo YH, Weston CJ, Lalor PF, Curbishley SM, Withers DR, Reynolds GM, Shetty S, Harki J, Shaw JC, Eksteen B (2010) Distinct roles for CCR4 and CXCR3 in the recruitment and positioning of regulatory T cells in the inflamed human liver. J Immunol 184(6):2886–2898.  https://doi.org/10.4049/jimmunol.0901216 CrossRefPubMedGoogle Scholar
  57. Piccirillo CA, Letterio JJ, Thornton AM, McHugh RS, Mamura M, Mizuhara H, Shevach EM (2002) CD4+ CD25+ regulatory T cells can mediate suppressor function in the absence of transforming growth factor β1 production and responsiveness. J Exp Med 196(2):237–246.  https://doi.org/10.1084/jem.20020590 CrossRefPubMedPubMedCentralGoogle Scholar
  58. Read S, Malmström V, Powrie F (2000) Cytotoxic T lymphocyte–associated antigen 4 plays an essential role in the function of CD25+ CD4+ regulatory cells that control intestinal inflammation. J Exp Med 192(2):295–302.  https://doi.org/10.1084/jem.192.2.295 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, Treuting P, Siewe L, Roers A, Henderson WR (2008) Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28(4):546–558.  https://doi.org/10.1016/j.immuni.2008.02.017 CrossRefPubMedGoogle Scholar
  60. Ruitenberg JJ, Boyce C, Hingorani R, Putnam A, Ghanekar SA (2011) Rapid assessment of in vitro expanded human regulatory T cell function. J Immunol Methods 372(1):95–106.  https://doi.org/10.1016/j.jim.2011.07.001 CrossRefPubMedGoogle Scholar
  61. 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
  62. Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY (2012) Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 150(1):29–38.  https://doi.org/10.1016/j.cell.2012.05.031 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Schmidt-Weber CB, Blaser K (2004) Regulation and role of transforming growth factor-β in immune tolerance induction and inflammation. Curr Opin Immunol 16(6):709–716.  https://doi.org/10.1016/j.coi.2004.09.008 CrossRefPubMedGoogle Scholar
  64. Seddon B, Mason D (1999) Regulatory T cells in the control of autoimmunity: the essential role of transforming growth factor β and interleukin 4 in the prevention of autoimmune thyroiditis in rats by peripheral CD4+ CD45RC− cells and CD4+ CD8− thymocytes. J Exp Med 189(2):279–288.  https://doi.org/10.1084/jem.189.2.279 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Stout RD, Suttles J (2004) Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol 76(3):509–513.  https://doi.org/10.1189/jlb.0504272 CrossRefPubMedPubMedCentralGoogle Scholar
  66. Taams LS, van Amelsfort JM, Tiemessen MM, Jacobs KM, de Jong EC, Akbar AN, Bijlsma JW, Lafeber FP (2005) Modulation of monocyte/macrophage function by human CD4+ CD25+ regulatory T cells. Hum Immunol 66(3):222–230.  https://doi.org/10.1016/j.humimm.2004.12.006 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S (2000) Immunologic self-tolerance maintained by CD25+ CD4+ regulatory T cells constitutively expressing cytotoxic T lymphocyte–associated antigen 4. J Exp Med 192(2):303–310CrossRefGoogle Scholar
  68. Tang Q, Lee K (2012) Regulatory T-cell therapy for transplantation: how many cells do we need? Curr Opin Organ Transplant 17(4):349–354.  https://doi.org/10.1097/MOT.0b013e328355a992 CrossRefPubMedGoogle Scholar
  69. Tang Q, Boden EK, Henriksen KJ, Bour-Jordan H, Bi M, Bluestone JA (2004) Distinct roles of CTLA-4 and TGF-β in CD4+ CD25+ regulatory T cell function. Eur J Immunol 34(11):2996–3005.  https://doi.org/10.1002/eji.200425143 CrossRefPubMedGoogle Scholar
  70. Thornton AM, Shevach EM (1998) CD4+ CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med 188(2):287–296CrossRefGoogle Scholar
  71. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, Shevach EM (2010) Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 184(7):3433–3441.  https://doi.org/10.4049/jimmunol.0904028 CrossRefPubMedPubMedCentralGoogle Scholar
  72. Tiemessen MM, Jagger AL, Evans HG, van Herwijnen MJ, John S, Taams LS (2007) CD4+ CD25+ Foxp3+ regulatory T cells induce alternative activation of human monocytes/macrophages. Proc Natl Acad Sci 104(49):19446–19451.  https://doi.org/10.1073/pnas.0706832104 CrossRefPubMedGoogle Scholar
  73. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3(5):541–547CrossRefGoogle Scholar
  74. Trzonkowski P, Bieniaszewska M, Juścińska J, Dobyszuk A, Krzystyniak A, Marek N, Myśliwska J, Hellmann A (2009) First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+ CD25+ CD127− T regulatory cells. Clin Immunol 133(1):22–26.  https://doi.org/10.1016/j.clim.2009.06.001 CrossRefPubMedGoogle Scholar
  75. Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, O’Garra A (2004) IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+ CD25+ regulatory T cells. J Immunol 172(10):5986–5993.  https://doi.org/10.4049/jimmunol.172.10.5986 CrossRefPubMedGoogle Scholar
  76. Wakkach A, Cottrez F, Groux H (2001) Differentiation of regulatory T cells 1 is induced by CD2 costimulation. J Immunol 167(6):3107–3113.  https://doi.org/10.4049/jimmunol.167.6.3107 CrossRefPubMedGoogle Scholar
  77. Watanabe N, Yi-Hong W, Lee HK, Ito T (2005) Hassall’s corpuscles instruct dendritic cells to induce CD4+ CD25+ regulatory T cells in human thymus. Nature 436(7054):1181.  https://doi.org/10.1038/nature03886 CrossRefPubMedGoogle Scholar
  78. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988CrossRefGoogle Scholar
  79. Weiner HL (2001) Induction and mechanism of action of transforming growth factor-β-secreting Th3 regulatory cells. Immunol Rev 182(1):207–214.  https://doi.org/10.1034/j.1600-065X.2001.1820117.x CrossRefPubMedGoogle Scholar
  80. Weiner M, Howard L (1997) Oral tolerance for the treatment of autoimmune diseases. Annu Rev Med 48(1):341–351.  https://doi.org/10.1146/annurev.med.48.1.341 CrossRefPubMedGoogle Scholar
  81. Weirather J, Hofmann U, Beyersdorf N, Ramos GC, Vogel B, Frey A, Ertl G, Kerkau T, Frantz S (2014) Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte/macrophage differentiation. Circ Res.  https://doi.org/10.1161/CIRCRESAHA.115.303895 CrossRefGoogle Scholar
  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.  https://doi.org/10.1126/science.1160062 CrossRefPubMedGoogle Scholar
  83. Yadav M, Bluestone JA, Stephan S (2013) Peripherally induced tregs–role in immune homeostasis and autoimmunity. Front Immunol 4(232):1–12.  https://doi.org/10.3389/fimmu.2013.00232 CrossRefGoogle Scholar
  84. Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA (2001) A role for TGF-β in the generation and expansion of CD4+ CD25+ regulatory T cells from human peripheral blood. J Immunol 166(12):7282–7289.  https://doi.org/10.4049/jimmunol.166.12.7282 CrossRefPubMedGoogle Scholar
  85. Yamazaki S, Bonito AJ, Spisek R, Dhodapkar M, Inaba K, Steinman RM (2007) Dendritic cells are specialized accessory cells along with TGF-β for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3− precursors. Blood 110(13):4293–4302.  https://doi.org/10.1182/blood-2007-05-088831 CrossRefPubMedPubMedCentralGoogle Scholar
  86. You S, Belghith M, Cobbold S, Alyanakian M-A, Gouarin C, Barriot S, Garcia C, Waldmann H, Bach J-F, Chatenoud L (2005) Autoimmune diabetes onset results from qualitative rather than quantitative age-dependent changes in pathogenic T-cells. Diabetes 54(5):1415–1422.  https://doi.org/10.2337/diabetes.54.5.1415 CrossRefPubMedGoogle Scholar
  87. Youhai-Chen VKK, Inobe J-i, Hafler DA, Weiner HL (1994) Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 265:1237.  https://doi.org/10.1126/science.7520605 CrossRefGoogle Scholar
  88. Zhang X, Izikson L, Liu L, Weiner HL (2001) Activation of CD25+ CD4+ regulatory T cells by oral antigen administration. J Immunol 167(8):4245–4253.  https://doi.org/10.4049/jimmunol.167.8.4245 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Interdisciplinary Program for BioengineeringSeoul National UniversitySeoulSouth Korea
  2. 2.School of Chemical and Biological EngineeringSeoul National UniversitySeoulSouth Korea
  3. 3.Institute of Chemical ProcessesSeoul National UniversitySeoulSouth Korea

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