Regulatory T cells and their roles in immune dysregulation and allergy

Immunologic Research

Volumn 58, Issue 2-3, 2014, Pages 358-368

  Pellerin, Laurence ^a   Jenks, Jennifer A ^a   Bégin, Philippe ^a   Bacchetta, Rosa ^a   Nadeau, Kari C ^a  

^a STANFORD UNIVERSITY   (United States)

Author keywords

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

Indexed keywords

CORTICOSTEROID; TRANSCRIPTION FACTOR FOXP3; ANTIALLERGIC AGENT;

ALLERGIC ASTHMA; ALLERGY; AUTOIMMUNE DISEASE; CELL FUNCTION; CELL THERAPY; ESSENTIAL GENE; GENE MUTATION; HUMAN; IMMUNE DYSREGULATION; IMMUNE RESPONSE; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; ANIMAL; DRUG EFFECTS; GENETICS; HYPERSENSITIVITY; IMMUNOLOGY; IMMUNOMODULATION; IMMUNOTHERAPY; METABOLISM; PHENOTYPE; T LYMPHOCYTE SUBPOPULATION;

ANIMALS; ANTI-ALLERGIC AGENTS; HUMANS; HYPERSENSITIVITY; IMMUNOMODULATION; IMMUNOTHERAPY; PHENOTYPE; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY;

EID: 84901421855     PISSN: 0257277X     EISSN: 15590755     Source Type: Journal    
DOI: 10.1007/s12026-014-8512-5     Document Type: Review

References (123)

1. Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol. 2012;4.
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.
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.
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. (Pubitemid 36432314)
5. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057-61. (Pubitemid 36222930)
6. Sansom DM, Walker LS. The role of CD28 and cytotoxic Tlymphocyte antigen-4 (CTLA-4) in regulatory T-cell biology. Immunol Rev. 2006;212:131-48. (Pubitemid 44116705)
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. (Pubitemid 44036276)
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.
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. (Pubitemid 46401429)
10. Forster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008;8:362-71. (Pubitemid 351595218)
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.
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. (Pubitemid 39094055)
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.
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.
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. (Pubitemid 40791235)
16. Mahmud SA, Manlove LS, Farrar MA. Interleukin-2 and STAT5 in regulatory T cell development and function. JAKSTAT. 2013;2:e23154.
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. (Pubitemid 38542009)
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.
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. (Pubitemid 40268196)
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. (Pubitemid 44092960)
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 tumorinduced regulatory T cells. Immunity. 2013;39:1057-69.
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. (Pubitemid 47175419)
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, Xlinked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20-1. (Pubitemid 32044513)
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. (Pubitemid 46279714)
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.
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.
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.
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.
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.
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.
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. (Pubitemid 47048022)
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.
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.
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. (Pubitemid 47423608)
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.
36. Zhou X, Bailey-Bucktrout S, Jeker LT, Bluestone JA. Plasticity of CD4(+) FoxP3(+) T cells. Curr Opin Immunol. 2009;21:281-5.
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.
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. (Pubitemid 46745377)
39. Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008;8:523-32.
40. Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM. Activated CD4+ CD25+ T cells selectively kill B lymphocytes. Blood. 2006;107:3925-32. (Pubitemid 43726798)
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. (Pubitemid 47628832)
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.
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. (Pubitemid 350131157)
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.
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. (Pubitemid 46919862)
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.
47. Sauer AV, Brigida I, Carriglio N, Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol. 2012;3:265.
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. (Pubitemid 46919868)
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.
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. (Pubitemid 41823872)
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. (Pubitemid 43727429)
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. (Pubitemid 34965886)
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. (Pubitemid 27458961)
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.
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. (Pubitemid 38621199)
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. (Pubitemid 40170889)
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.
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. (Pubitemid 37468107)
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. (Pubitemid 38405905)
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. (Pubitemid 43725808)
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.
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. (Pubitemid 37120544)
63. Gregori S, Tomasoni D, Pacciani V, Scirpoli M, Battaglia M, Magnani CF, Hauben E, Roncarolo MG. Differentiation of type1 T regulatory cells (Tr1) by tolerogenic DC-10 requires the IL-10-dependent ILT4/HLA-G pathway. Blood. 2010;116:935-44.
64. Moreau P, Adrian-Cabestre F, Menier C, Guiard V, Gourand L, Dausset J, Carosella ED, Paul P. IL-10 selectively induces HLAG expression in human trophoblasts and monocytes. Int Immunol. 1999;11:803-11. (Pubitemid 29237771)
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.
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.
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.
68. Shalev I, Schmelzle M, Robson SC, Levy G. Making sense of regulatory T cell suppressive function. Semin Immunol. 2011;23:282-92.
69. Bacchetta R, Notarangelo LD. Immunodeficiency with autoimmunity: beyond the paradox. Front Immunol. 2013;4:77.
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.
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.
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.
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.
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.
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.
76. Marwaha AK, Leung NJ, McMurchy AN, Levings MK. TH17 Cells in autoimmunity and immunodeficiency: protective or pathogenic? Front Immunol. 2012;3:129.
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.
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.
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.
80. Catucci M, Castiello MC, Pala F, Bosticardo M, Villa A. Autoimmunity in wiskott-Aldrich syndrome: an unsolved enigma. Front Immunol. 2012;3:209.
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.
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 inter-leukin- 10 receptor. N Engl J Med. 2009;361:2033-45.
83. Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138-46. (Pubitemid 26074503)
84. Akdis CA, Blaser K, Akdis M. Apoptosis in tissue inflammation and allergic disease. Curr Opin Immunol. 2004;16:717-23. (Pubitemid 39423659)
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 allergeninduced late-phase cutaneous reactions in atopic subjects. J Immunol. 1997;158:5050-7. (Pubitemid 127483832)
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.
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.
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.
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.
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. (Pubitemid 39233690)
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. (Pubitemid 38264178)
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.
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.
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.
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. (Pubitemid 351197095)
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.
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.
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. (Pubitemid 46654192)
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.
100. Smyth LJ, Eustace A, Kolsum U, Blaikely J, Singh D. Increased airway T regulatory cells in asthmatic subjects. Chest. 2010;138:905-12.
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.
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.
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. (Pubitemid 38780411)
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.
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.
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.
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.
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. (Pubitemid 41017653)
109. Syed A, Kohli A, Nadeau KC. Food allergy diagnosis and therapy: where are we now? Immunotherapy. 2013;5:931-44.
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.
111. Fischbach MA, Bluestone JA, Lim WA. Cell-based therapeutics: the next pillar of medicine. Sci Transl Med. 2013;5:179ps177.
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.
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. (Pubitemid 44893795)
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-Stanford 2-mAb complexes: induction of resistance to EAE and longterm acceptance of islet allografts without immunosuppression. J Exp Med. 2009;206:751-60.
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.
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.
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.
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.
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.
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.
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.
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 HLAmismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118:282-8.
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.