Immunologic Research

, Volume 58, Issue 2–3, pp 358–368 | Cite as

Regulatory T cells and their roles in immune dysregulation and allergy

  • Laurence Pellerin
  • Jennifer A. Jenks
  • Philippe Bégin
  • Rosa Bacchetta
  • Kari C. Nadeau
IMMUNOLOGY AT STANFORD UNIVERSITY

Abstract

The main function of the immune system is to fight off potential infections, but also to maintain its activity below a level that would trigger self-reactivity. Regulatory T cells (Tregs) such as forkhead box P3+ (FOXP3) Tregs and type 1 regulatory T cells (Tr1) play an essential role in this active process, using several distinct suppressive mechanisms. A wide range of pathologies have been associated with altered Treg cell function. This is best exemplified by the impact of mutations of genes essential for Treg function and the associated autoimmune syndromes. This review summarizes the main features of different subtypes of Tregs and focuses on the clinical implications of their altered function in human studies. More specifically, we discuss abnormalities affecting FOXP3+ Tregs and Tr1 cells that will lead to autoimmune manifestations and/or allergic reactions, and the potential therapeutic use of Tregs.

Keywords

Regulatory T cells Type 1 regulatory T cells FOXP3 Allergy Immune dysregulation 

References

  1. 1.
    Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol. 2012;4.Google Scholar
  2. 2.
    Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol. 2013;14:307–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. 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. 1995;155:1151–64.PubMedGoogle Scholar
  4. 4.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.PubMedCrossRefGoogle Scholar
  6. 6.
    Sansom DM, Walker LS. The role of CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol Rev. 2006;212:131–48.PubMedCrossRefGoogle Scholar
  7. 7.
    Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, de St Fazekas GB, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–11.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, Parizot C, Taflin C, Heike T, Valeyre D, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30:899–911.PubMedCrossRefGoogle Scholar
  9. 9.
    Bono MR, Elgueta R, Sauma D, Pino K, Osorio F, Michea P, Fierro A, Rosemblatt M. The essential role of chemokines in the selective regulation of lymphocyte homing. Cytokine Growth Factor Rev. 2007;18:33–43.PubMedCrossRefGoogle Scholar
  10. 10.
    Forster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008;8:362–71.PubMedCrossRefGoogle Scholar
  11. 11.
    Afshar R, Strassner JP, Seung E, Causton B, Cho JL, Harris RS, Hamilos DL, Medoff BD, Luster AD. Compartmentalized chemokine-dependent regulatory T-cell inhibition of allergic pulmonary inflammation. J Allergy Clin Immunol. 2013;131:1644–52.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity. 2004;21:267–77.PubMedCrossRefGoogle Scholar
  13. 13.
    Moran AE, Holzapfel KL, Xing Y, Cunningham NR, Maltzman JS, Punt J, Hogquist KA. T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. J Exp Med. 2011;208:1279–89.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Hwang S, Song KD, Lesourne R, Lee J, Pinkhasov J, Li L, El-Khoury D, Love PE. Reduced TCR signaling potential impairs negative selection but does not result in autoimmune disease. J Exp Med. 2012;209:1781–95.PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Levings MK, Roncarolo MG. Phenotypic and functional differences between human CD4+ CD25+ and type 1 regulatory T cells. Curr Top Microbiol Immunol. 2005;293:303–26.PubMedGoogle Scholar
  16. 16.
    Mahmud SA, Manlove LS, Farrar MA. Interleukin-2 and STAT5 in regulatory T cell development and function. JAKSTAT. 2013;2:e23154.PubMedCentralPubMedGoogle Scholar
  17. 17.
    Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+ CD25− T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004;172:5149–53.PubMedCrossRefGoogle Scholar
  18. 18.
    Hanabuchi S, Ito T, Park WR, Watanabe N, Shaw JL, Roman E, Arima K, Wang YH, Voo KS, Cao W, et al. Thymic stromal lymphopoietin-activated plasmacytoid dendritic cells induce the generation of FOXP3+ regulatory T cells in human thymus. J Immunol. 2010;184:2999–3007.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Tai X, Cowan M, Feigenbaum L, Singer A. CD28 costimulation of developing thymocytes induces Foxp3 expression and regulatory T cell differentiation independently of interleukin 2. Nat Immunol. 2005;6:152–62.PubMedCrossRefGoogle Scholar
  20. 20.
    Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L, Han A, Ziegler SF, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006;126:375–87.PubMedCrossRefGoogle Scholar
  21. 21.
    Hossain DM, Panda AK, Manna A, Mohanty S, Bhattacharjee P, Bhattacharyya S, Saha T, Chakraborty S, Kar RK, Das T, et al. FoxP3 acts as a cotranscription factor with STAT3 in tumor-induced regulatory T cells. Immunity. 2013;39:1057–69.PubMedCrossRefGoogle Scholar
  22. 22.
    Komatsu N, Hori S. Full restoration of peripheral Foxp3+ regulatory T cell pool by radioresistant host cells in scurfy bone marrow chimeras. Proc Natl Acad Sci USA. 2007;104:8959–64.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20–1.PubMedCrossRefGoogle Scholar
  24. 24.
    Gavin MA, Rasmussen JP, Fontenot JD, Vasta V, Manganiello VC, Beavo JA, Rudensky AY. Foxp3-dependent programme of regulatory T-cell differentiation. Nature. 2007;445:771–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Zhang Y, Maksimovic J, Naselli G, Qian J, Chopin M, Blewitt ME, Oshlack A, Harrison LC. Genome-wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells. Blood. 2013;122:2823–36.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Allan SE, Alstad AN, Merindol N, Crellin NK, Amendola M, Bacchetta R, Naldini L, Roncarolo MG, Soudeyns H, Levings MK. Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol Ther. 2008;16:194–202.PubMedCrossRefGoogle Scholar
  27. 27.
    Passerini L, Mel ER, Sartirana C, Fousteri G, Bondanza A, Naldini L, Roncarolo MG, Bacchetta R. CD4+ T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci Transl Med. 2013;5:215ra174.PubMedCrossRefGoogle Scholar
  28. 28.
    Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37:785–99.PubMedCrossRefGoogle Scholar
  29. 29.
    Passerini L, Santoni de Sio FR, Roncarolo MG, Bacchetta R. Forkhead box P3: the peacekeeper of the immune system. Int Rev Immunol. 2014;33(2):129–45.Google Scholar
  30. 30.
    Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010;463:808–12.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Kim HP, Leonard WJ. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med. 2007;204:1543–51.PubMedCentralPubMedGoogle Scholar
  32. 32.
    Polansky JK, Kretschmer K, Freyer J, Floess S, Garbe A, Baron U, Olek S, Hamann A, von Boehmer H, Huehn J. DNA methylation controls Foxp3 gene expression. Eur J Immunol. 2008;38:1654–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Wieczorek G, Asemissen A, Model F, Turbachova I, Floess S, Liebenberg V, Baron U, Stauch D, Kotsch K, Pratschke J, et al. Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue. Cancer Res. 2009;69:599–608.PubMedCrossRefGoogle Scholar
  34. 34.
    Baron U, Floess S, Wieczorek G, Baumann K, Grutzkau A, Dong J, Thiel A, Boeld TJ, Hoffmann P, Edinger M, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol. 2007;37:2378–89.PubMedCrossRefGoogle Scholar
  35. 35.
    Oestreich KJ, Weinmann AS. Encoding stability versus flexibility: lessons learned from examining epigenetics in T helper cell differentiation. Curr Top Microbiol Immunol. 2012;356:145–64.PubMedGoogle Scholar
  36. 36.
    Zhou X, Bailey-Bucktrout S, Jeker LT, Bluestone JA. Plasticity of CD4(+) FoxP3(+) T cells. Curr Opin Immunol. 2009;21:281–5.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Zhou X, Jeker LT, Fife BT, Zhu S, Anderson MS, McManus MT, Bluestone JA. Selective miRNA disruption in T reg cells leads to uncontrolled autoimmunity. J Exp Med. 2008;205:1983–91.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8:277–84.PubMedCrossRefGoogle Scholar
  39. 39.
    Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523–32.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+ CD25+ T cells selectively kill B lymphocytes. Blood. 2006;107:3925–32.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity. 2007;27:635–46.PubMedCrossRefGoogle Scholar
  42. 42.
    Loebbermann J, Thornton H, Durant L, Sparwasser T, Webster KE, Sprent J, Culley FJ, Johansson C, Openshaw PJ. Regulatory T cells expressing granzyme B play a critical role in controlling lung inflammation during acute viral infection. Mucosal Immunol. 2012;5:161–72.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Ren X, Ye F, Jiang Z, Chu Y, Xiong S, Wang Y. Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4(+)CD25(+) regulatory T cells. Cell Death Differ. 2007;14:2076–84.PubMedCrossRefGoogle Scholar
  44. 44.
    Collison LW, Pillai MR, Chaturvedi V, Vignali DA. Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol. 2009;182:6121–8.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K, Linden J, Oukka M, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204:1257–65.PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Hausler SF, Montalban del Barrio I, Strohschein J, Anoop Chandran P, Engel JB, Honig A, Ossadnik M, Horn E, Fischer B, Krockenberger M, et al. Ectonucleotidases CD39 and CD73 on OvCA cells are potent adenosine-generating enzymes responsible for adenosine receptor 2A-dependent suppression of T cell function and NK cell cytotoxicity. Cancer Immunol Immunother. 2011;60:1405–18.PubMedCrossRefGoogle Scholar
  47. 47.
    Sauer AV, Brigida I, Carriglio N, Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol. 2012;3:265.PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Bopp T, Becker C, Klein M, Klein-Hessling S, Palmetshofer A, Serfling E, Heib V, Becker M, Kubach J, Schmitt S, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med. 2007;204:1303–10.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Tadokoro CE, Shakhar G, Shen S, Ding Y, Lino AC, Maraver A, Lafaille JJ, Dustin ML. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med. 2006;203:505–11.PubMedCentralPubMedCrossRefGoogle Scholar
  50. 50.
    Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006;7:83–92.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Oderup C, Cederbom L, Makowska A, Cilio CM, Ivars F. Cytotoxic T lymphocyte antigen-4-dependent down-modulation of costimulatory molecules on dendritic cells in CD4+ CD25+ regulatory T-cell-mediated suppression. Immunology. 2006;118:240–9.PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Bacchetta R, Sartirana C, Levings MK, Bordignon C, Narula S, Roncarolo MG. Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol. 2002;32:2237–45.PubMedCrossRefGoogle Scholar
  53. 53.
    Groux H, O’Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997;389:737–42.PubMedCrossRefGoogle Scholar
  54. 54.
    Cottrez F, Hurst SD, Coffman RL, Groux H. T regulatory cells 1 inhibit a Th2-specific response in vivo. J Immunol. 2000;165:4848–53.PubMedCrossRefGoogle Scholar
  55. 55.
    Vieira PL, Christensen JR, Minaee S, O’Neill EJ, Barrat FJ, Boonstra A, Barthlott T, Stockinger B, Wraith DC, O’Garra A. 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. 2004;172:5986–93.PubMedCrossRefGoogle Scholar
  56. 56.
    Levings MK, Gregori S, Tresoldi E, Cazzaniga S, Bonini C, Roncarolo MG. Differentiation of Tr1 cells by immature dendritic cells requires IL-10 but not CD25+ CD4+ Tr cells. Blood. 2005;105:1162–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Passerini L, Di Nunzio S, Gregori S, Gambineri E, Cecconi M, Seidel MG, Cazzola G, Perroni L, Tommasini A, Vignola S, et al. Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. Eur J Immunol. 2011;41:1120–31.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Cobbold SP, Nolan KF, Graca L, Castejon R, Le Moine A, Frewin M, Humm S, Adams E, Thompson S, Zelenika D, et al. Regulatory T cells and dendritic cells in transplantation tolerance: molecular markers and mechanisms. Immunol Rev. 2003;196:109–24.PubMedCrossRefGoogle Scholar
  59. 59.
    Kohyama M, Sugahara D, Sugiyama S, Yagita H, Okumura K, Hozumi N. Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen. Proc Natl Acad Sci USA. 2004;101:4192–7.PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Rahmoun M, Foussat A, Groux H, Pene J, Yssel H, Chanez P. Enhanced frequency of CD18- and CD49b-expressing T cells in peripheral blood of asthmatic patients correlates with disease severity. Int Arch Allergy Immunol. 2006;140:139–49.PubMedCrossRefGoogle Scholar
  61. 61.
    Gagliani N, Magnani CF, Huber S, Gianolini ME, Pala M, Licona-Limon P, Guo B, Herbert DR, Bulfone A, Trentini F, et al. Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cells. Nat Med. 2013;19:739–46.PubMedCrossRefGoogle Scholar
  62. 62.
    Manavalan JS, Rossi PC, Vlad G, Piazza F, Yarilina A, Cortesini R, Mancini D, Suciu-Foca N. High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells. Transpl Immunol. 2003;11:245–58.PubMedCrossRefGoogle Scholar
  63. 63.
    Gregori S, Tomasoni D, Pacciani V, Scirpoli M, Battaglia M, Magnani CF, Hauben E, Roncarolo MG. Differentiation of type 1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood. 2010;116:935–44.PubMedCrossRefGoogle Scholar
  64. 64.
    Moreau P, Adrian-Cabestre F, Menier C, Guiard V, Gourand L, Dausset J, Carosella ED, Paul P. IL-10 selectively induces HLA-G expression in human trophoblasts and monocytes. Int Immunol. 1999;11:803–11.PubMedCrossRefGoogle Scholar
  65. 65.
    Gregori S, Goudy KS, Roncarolo MG. The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells. Front Immunol. 2012;3:30.PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Jackson EK, Johnson JT, Gorelik E, Lang S, Whiteside TL. Adenosine and prostaglandin E2 cooperate in the suppression of immune responses mediated by adaptive regulatory T cells. J Biol Chem. 2010;285:27571–80.PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Magnani CF, Alberigo G, Bacchetta R, Serafini G, Andreani M, Roncarolo MG, Gregori S. Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells. Eur J Immunol. 2011;41:1652–62.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Shalev I, Schmelzle M, Robson SC, Levy G. Making sense of regulatory T cell suppressive function. Semin Immunol. 2011;23:282–92.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Bacchetta R, Notarangelo LD. Immunodeficiency with autoimmunity: beyond the paradox. Front Immunol. 2013;4:77.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol. 2012;3:211.PubMedCentralPubMedCrossRefGoogle Scholar
  71. 71.
    Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, Dagna-Bricarelli F, Sartirana C, Matthes-Martin S, Lawitschka A, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest. 2006;116:1713–22.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Barzaghi F, Passerini L, Gambineri E, Ciullini Mannurita S, Cornu T, Kang ES, Choe YH, Cancrini C, Corrente S, Ciccocioppo R, et al. Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun. 2012;38:49–58.PubMedCrossRefGoogle Scholar
  73. 73.
    Di Nunzio S, Cecconi M, Passerini L, McMurchy AN, Baron U, Turbachova I, Vignola S, Valencic E, Tommasini A, Junker A, et al. Wild-type FOXP3 is selectively active in CD4+ CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood. 2009;114:4138–41.PubMedCrossRefGoogle Scholar
  74. 74.
    Seidel MG, Fritsch G, Lion T, Jurgens B, Heitger A, Bacchetta R, Lawitschka A, Peters C, Gadner H, Matthes-Martin S. Selective engraftment of donor CD4+ 25high FOXP3-positive T cells in IPEX syndrome after nonmyeloablative hematopoietic stem cell transplantation. Blood. 2009;113:5689–91.PubMedCrossRefGoogle Scholar
  75. 75.
    Passerini L, Olek S, Di Nunzio S, Barzaghi F, Hambleton S, Abinun M, Tommasini A, Vignola S, Cipolli M, Amendola M, et al. Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability. J Allergy Clin Immunol. 2011;128(1376–1379):e1371.Google Scholar
  76. 76.
    Marwaha AK, Leung NJ, McMurchy AN, Levings MK. TH17 Cells in autoimmunity and immunodeficiency: protective or pathogenic? Front Immunol. 2012;3:129.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Kinnunen T, Chamberlain N, Morbach H, Choi J, Kim S, Craft J, Mayer L, Cancrini C, Passerini L, Bacchetta R, et al. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood. 2013;121:1595–603.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Goudy K, Aydin D, Barzaghi F, Gambineri E, Vignoli M, Ciullini Mannurita S, Doglioni C, Ponzoni M, Cicalese MP, Assanelli A, et al. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity. Clin Immunol. 2013;146:248–61.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Jenks JA, Seki S, Kanai T, Huang J, Morgan AA, Scalco RC, Nath R, Bucayu R, Wit JM, Al-Herz W, et al. Differentiating the roles of STAT5B and STAT5A in human CD4+ T cells. Clin Immunol. 2013;148:227–36.PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Catucci M, Castiello MC, Pala F, Bosticardo M, Villa A. Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol. 2012;3:209.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev. 2008;224:166–82.PubMedCrossRefGoogle Scholar
  82. 82.
    Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F, Perro M, Diestelhorst J, Allroth A, Murugan D, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–45.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138–46.PubMedCrossRefGoogle Scholar
  84. 84.
    Akdis CA, Blaser K, Akdis M. Apoptosis in tissue inflammation and allergic disease. Curr Opin Immunol. 2004;16:717–23.PubMedCrossRefGoogle Scholar
  85. 85.
    Ying S, Meng Q, Barata LT, Robinson DS, Durham SR, Kay AB. Associations between IL-13 and IL-4 (mRNA and protein), vascular cell adhesion molecule-1 expression, and the infiltration of eosinophils, macrophages, and T cells in allergen-induced late-phase cutaneous reactions in atopic subjects. J Immunol. 1997;158:5050–7.PubMedGoogle Scholar
  86. 86.
    Zhang L, Zhang Y, Desrosiers M, Wang C, Zhao Y, Han D. Genetic association study of FOXP3 polymorphisms in allergic rhinitis in a Chinese population. Hum Immunol. 2009;70:930–4.PubMedCrossRefGoogle Scholar
  87. 87.
    Bottema RW, Kerkhof M, Reijmerink NE, Koppelman GH, Thijs C, Stelma FF, Smit HA, Brunekreef B, van Schayck CP, Postma DS. X-chromosome Forkhead box P3 polymorphisms associate with atopy in girls in three Dutch birth cohorts. Allergy. 2010;65:865–74.PubMedCrossRefGoogle Scholar
  88. 88.
    Fodor E, Garaczi E, Polyanka H, Koreck A, Kemeny L, Szell M. The rs3761548 polymorphism of FOXP3 is a protective genetic factor against allergic rhinitis in the Hungarian female population. Hum Immunol. 2011;72:926–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Runyon RS, Cachola LM, Rajeshuni N, Hunter T, Garcia M, Ahn R, Lurmann F, Krasnow R, Jack LM, Miller RL, et al. Asthma discordance in twins is linked to epigenetic modifications of T cells. PLoS One. 2012;7:e48796.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Grindebacke H, Wing K, Andersson AC, Suri-Payer E, Rak S, Rudin A. Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season. Clin Exp Allergy. 2004;34:1364–72.PubMedCrossRefGoogle Scholar
  91. 91.
    Ling EM, Smith T, Nguyen XD, Pridgeon C, Dallman M, Arbery J, Carr VA, Robinson DS. Relation of CD4+ CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet. 2004;363:608–15.PubMedCrossRefGoogle Scholar
  92. 92.
    Kinoshita T, Baatjes A, Smith SG, Dua B, Watson R, Kawayama T, Larche M, Gauvreau GM, O’Byrne PM. Natural regulatory T cells in isolated early responders compared with dual responders with allergic asthma. J Allergy Clin Immunol. 2014;133(3):696–703.Google Scholar
  93. 93.
    Lee JH, Yu HH, Wang LC, Yang YH, Lin YT, Chiang BL. The levels of CD4+ CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin Exp Immunol. 2007;148:53–63.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Lin YL, Shieh CC, Wang JY. The functional insufficiency of human CD4+ CD25 high T-regulatory cells in allergic asthma is subjected to TNF-alpha modulation. Allergy. 2008;63:67–74.PubMedCrossRefGoogle Scholar
  95. 95.
    Moniuszko M, Kowal K, Zukowski S, Dabrowska M, Bodzenta-Lukaszyk A. Frequencies of circulating CD4+ CD25+ CD127low cells in atopics are altered by bronchial allergen challenge. Eur J Clin Invest. 2008;38:201–4.PubMedCrossRefGoogle Scholar
  96. 96.
    Nguyen KD, Fohner A, Booker JD, Dong C, Krensky AM, Nadeau KC. XCL1 enhances regulatory activities of CD4+ CD25(high) CD127(low/−) T cells in human allergic asthma. J Immunol. 2008;181:5386–95.PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Nguyen KD, Vanichsarn C, Fohner A, Nadeau KC. Selective deregulation in chemokine signaling pathways of CD4+ CD25(hi)CD127(lo)/(−) regulatory T cells in human allergic asthma. J Allergy Clin Immunol. 2009;123(933–939):e910.Google Scholar
  98. 98.
    Hartl D, Koller B, Mehlhorn AT, Reinhardt D, Nicolai T, Schendel DJ, Griese M, Krauss-Etschmann S. Quantitative and functional impairment of pulmonary CD4+ CD25hi regulatory T cells in pediatric asthma. J Allergy Clin Immunol. 2007;119:1258–66.PubMedCrossRefGoogle Scholar
  99. 99.
    Thunberg S, Gafvelin G, Nord M, Gronneberg R, Grunewald J, Eklund A, van Hage M. Allergen provocation increases TH2-cytokines and FOXP3 expression in the asthmatic lung. Allergy. 2010;65:311–8.PubMedCrossRefGoogle Scholar
  100. 100.
    Smyth LJ, Eustace A, Kolsum U, Blaikely J, Singh D. Increased airway T regulatory cells in asthmatic subjects. Chest. 2010;138:905–12.PubMedCrossRefGoogle Scholar
  101. 101.
    Kim YM, Munoz A, Hwang PH, Nadeau KC. Migration of regulatory T cells toward airway epithelial cells is impaired in chronic rhinosinusitis with nasal polyposis. Clin Immunol. 2010;137:111–21.PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Martin H, Reuter S, Dehzad N, Heinz A, Bellinghausen I, Saloga J, Haasler I, Korn S, Jonuleit H, Buhl R, et al. CD4-mediated regulatory T-cell activation inhibits the development of disease in a humanized mouse model of allergic airway disease. J Allergy Clin Immunol. 2012;129:521–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Akdis M, Verhagen J, Taylor A, Karamloo F, Karagiannidis C, Crameri R, Thunberg S, Deniz G, Valenta R, Fiebig H, et al. Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells. J Exp Med. 2004;199:1567–75.PubMedCentralPubMedCrossRefGoogle Scholar
  104. 104.
    Meiler F, Zumkehr J, Klunker S, Ruckert B, Akdis CA, Akdis M. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med. 2008;205:2887–98.PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, Shreffler WG, Steele P, Henry KA, Adair M, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009;124:292–300.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Scadding GW, Shamji MH, Jacobson MR, Lee DI, Wilson D, Lima MT, Pitkin L, Pilette C, Nouri-Aria K, Durham SR. Sublingual grass pollen immunotherapy is associated with increases in sublingual Foxp3-expressing cells and elevated allergen-specific immunoglobulin G4, immunoglobulin A and serum inhibitory activity for immunoglobulin E-facilitated allergen binding to B cells. Clin Exp Allergy. 2010;40:598–606.PubMedGoogle Scholar
  107. 107.
    Swamy RS, Reshamwala N, Hunter T, Vissamsetti S, Santos CB, Baroody FM, Hwang PH, Hoyte EG, Garcia MA, Nadeau KC. Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy. J Allergy Clin Immunol. 2012;130(215–224):e217.Google Scholar
  108. 108.
    Jutel M, Akdis M, Blaser K, Akdis CA. Are regulatory T cells the target of venom immunotherapy? Curr Opin Allergy Clin Immunol. 2005;5:365–9.PubMedCrossRefGoogle Scholar
  109. 109.
    Syed A, Kohli A, Nadeau KC. Food allergy diagnosis and therapy: where are we now? Immunotherapy. 2013;5:931–44.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Syed A, Garcia MA, Lyu SC, Bucayu R, Kohli A, Ishida S, Berglund JP, Tsai M, Maecker H, O’Riordan G, et al. Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3). J Allergy Clin Immunol. 2014;133(500–510):e511.Google Scholar
  111. 111.
    Fischbach MA, Bluestone JA, Lim WA. Cell-based therapeutics: the next pillar of medicine. Sci Transl Med. 2013;5:179ps177.CrossRefGoogle Scholar
  112. 112.
    Schneidawind D, Pierini A, Negrin RS. Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. Blood. 2013;122:3116–21.PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG. Rapamycin promotes expansion of functional CD4+ CD25+ FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006;177:8338–47.PubMedCrossRefGoogle Scholar
  114. 114.
    Webster KE, Walters S, Kohler RE, Mrkvan T, Boyman O, Surh CD, Grey ST, Sprent J. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med. 2009;206:751–60.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Shatry A, Levy RB. In situ activation and expansion of host tregs: a new approach to enhance donor chimerism and stable engraftment in major histocompatibility complex-matched allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15:785–94.PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Nadeau KC, Kohli A, Iyengar S, DeKruyff RH, Umetsu DT. Oral immunotherapy and anti-IgE antibody-adjunctive treatment for food allergy. Immunol Allergy Clin North Am. 2012;32:111–33.PubMedCrossRefGoogle Scholar
  117. 117.
    Bacchetta R, Gregori S, Serafini G, Sartirana C, Schulz U, Zino E, Tomiuk S, Jansen U, Ponzoni M, Paties CT, et al. Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy. Haematologica. 2010;95:2134–43.PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Desreumaux P, Foussat A, Allez M, Beaugerie L, Hebuterne X, Bouhnik Y, Nachury M, Brun V, Bastian H, Belmonte N, et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn’s disease. Gastroenterology. 2012;143(1207–1217):e1201–2.Google Scholar
  119. 119.
    Bacchetta R, Lucarrelli B, Sartirana C, Gregori S, Stanghellini L, Terasa M, Miqueu P, Tomiuk S, Hernandez-Fuentes M, Gianolini ME, Greco R, Bernardi M, Zappone E, Rossini S, Janssen U, Ambrosi A, Salomoni M, Peccatori J, Ciceri F, Roncarolo MG. Immunological outcome in haploidentical-HSC transplanted patients treated with IL-10-anergized donor T cells. Front Immunol. 2014;5:16.PubMedCentralPubMedCrossRefGoogle Scholar
  120. 120.
    Putnam AL, Safinia N, Medvec A, Laszkowska M, Wray M, Mintz MA, Trotta E, Szot GL, Liu W, Lares A, et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am J Transplant. 2013;13:3010–20.PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Sawitzki B, Brunstein C, Meisel C, Schumann J, Vogt K, Appelt C, Curtsinger JM, Verneris MR, Miller JS, Wagner JE, et al. Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood toll-like receptor 5 mRNA expression. Biol Blood Marrow Transplant. 2014;20(2):173–82.Google Scholar
  122. 122.
    Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, et al. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118:282–8.PubMedCentralPubMedCrossRefGoogle Scholar
  123. 123.
    Andolfi G, Fousteri G, Rossetti M, Magnani CF, Jofra T, Locafaro G, Bondanza A, Gregori S, Roncarolo MG. Enforced IL-10 expression confers type 1 regulatory T cell (Tr1) phenotype and function to human CD4(+) T cells. Mol Ther. 2012;20:1778–90.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Laurence Pellerin
    • 1
  • Jennifer A. Jenks
    • 1
  • Philippe Bégin
    • 1
  • Rosa Bacchetta
    • 1
  • Kari C. Nadeau
    • 1
  1. 1.Division of Pediatric Immunology and AllergyStanford UniversityStanfordUSA

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