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Immunologic Research
Published in: Immunologic Research 2-3/2014

01-05-2014 | IMMUNOLOGY AT STANFORD UNIVERSITY

Regulatory T cells and their roles in immune dysregulation and allergy

Authors: Laurence Pellerin, Jennifer A. Jenks, Philippe Bégin, Rosa Bacchetta, Kari C. Nadeau

Published in: Immunologic Research | Issue 2-3/2014

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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.
Literature
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.PubMedCrossRef
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.PubMed
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.PubMedCrossRef
5.
Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299:1057–61.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
10.
Forster R, Davalos-Misslitz AC, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008;8:362–71.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMed
16.
Mahmud SA, Manlove LS, Farrar MA. Interleukin-2 and STAT5 in regulatory T cell development and function. JAKSTAT. 2013;2:e23154.PubMedCentralPubMed
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMed
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMed
36.
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
39.
40.
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
47.
Sauer AV, Brigida I, Carriglio N, Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol. 2012;3:265.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
68.
69.
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
80.
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
83.
Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996;17:138–46.PubMedCrossRef
84.
Akdis CA, Blaser K, Akdis M. Apoptosis in tissue inflammation and allergic disease. Curr Opin Immunol. 2004;16:717–23.PubMedCrossRef
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.PubMed
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
100.
Smyth LJ, Eustace A, Kolsum U, Blaikely J, Singh D. Increased airway T regulatory cells in asthmatic subjects. Chest. 2010;138:905–12.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMed
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.PubMedCrossRef
109.
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.CrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
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 HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;118:282–8.PubMedCentralPubMedCrossRef
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.PubMedCentralPubMedCrossRef
Metadata
Title
Regulatory T cells and their roles in immune dysregulation and allergy
Authors
Laurence Pellerin
Jennifer A. Jenks
Philippe Bégin
Rosa Bacchetta
Kari C. Nadeau
Publication date
01-05-2014
Publisher
Springer US
Published in
Immunologic Research / Issue 2-3/2014
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI
https://doi.org/10.1007/s12026-014-8512-5

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