Author Correction: Antigen-specific regulatory T-cell responses against aeroantigens and their role in allergy (Mucosal Immunology, (2018), 11, 6, (1537-1550), 10.1038/s41385-018-0038-z);Antigen-specific regulatory T-cell responses against aeroantigens and their role in allergy

Mucosal Immunology

Volumn 11, Issue 6, 2018, Pages 1537-1550

  Bacher, Petra ^a   Scheffold, Alexander ^b  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^b UNIVERSITY HOSPITAL SCHLESWIG HOLSTEIN   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

AEROANTIGEN; ANTIGEN; INTERLEUKIN 10; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FOXP3; UNCLASSIFIED DRUG; ALLERGEN; IMMUNOGLOBULIN E;

ALLERGY; ANTIGEN FUNCTION; ANTIGEN SPECIFICITY; CELL EXPANSION; CELLULAR IMMUNITY; CLONAL ANERGY; CYTOKINE PRODUCTION; DRUG DESIGN; ENVIRONMENTAL FACTOR; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOPATHOGENESIS; IMMUNOTHERAPY; MAJOR HISTOCOMPATIBILITY COMPLEX; MUCOSAL IMMUNITY; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; ANIMAL; DESENSITIZATION; HYPERSENSITIVITY; IMMUNOLOGY; METABOLISM; PARTICULATE MATTER; PROCEDURES; TH2 CELL;

ALLERGENS; ANIMALS; DESENSITIZATION, IMMUNOLOGIC; HUMANS; HYPERSENSITIVITY; IMMUNE TOLERANCE; IMMUNITY, MUCOSAL; IMMUNOGLOBULIN E; PARTICULATE MATTER; T-CELL ANTIGEN RECEPTOR SPECIFICITY; T-LYMPHOCYTES, REGULATORY; TH2 CELLS;

EID: 85047945557     PISSN: 19330219     EISSN: 19353456     Source Type: Journal    
DOI: 10.1038/s41385-019-0137-5     Document Type: Erratum

References (188)

1. Alexander, K. L., Targan, S. R. & Elson, C. O. 3rd Microbiota activation and regulation of innate and adaptive immunity. Immunol. Rev. 260, 206–220 (2014)
2. Platts-Mills, T. A. & Woodfolk, J. A. Allergens and their role in the allergic immune response. Immunol. Rev. 242, 51–68 (2011)
3. Wambre, E. & Jeong, D. Oral tolerance development and maintenance. Immunol. Allergy Clin. North Am. 38, 27–37 (2018)
4. Russler-Germain, E. V., Rengarajan, S. & Hsieh, C. S. Antigen-specific regulatory T-cell responses to intestinal microbiota. Mucosal Immunol. 10, 1375–1386 (2017)
5. Lambrecht, B. N. & Hammad, H. The immunology of the allergy epidemic and the hygiene hypothesis. Nat. Immunol. 18, 1076–1083 (2017)
6. Platts-Mills, T. A. The allergy epidemics: 1870-2010. J. Allergy Clin. Immunol. 136, 3–13 (2015)
7. Gelfand, E. W., Joetham, A., Wang, M., Takeda, K. & Schedel, M. Spectrum of T-lymphocyte activities regulating allergic lung inflammation. Immunol. Rev. 278, 63–86 (2017)
8. Nakayama, T. et al. Th2 cells in health and disease. Annu. Rev. Immunol. 35, 53–84 (2017)
9. Shamji, M. H. & Durham, S. R. Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers. J. Allergy Clin. Immunol. 140, 1485–1498 (2017)
10. van de Veen, W., Wirz, O. F., Globinska, A. & Akdis, M. Novel mechanisms in immune tolerance to allergens during natural allergen exposure and allergen-specific immunotherapy. Curr. Opin. Immunol. 48, 74–81 (2017)
11. Wambre, E. Effect of allergen-specific immunotherapy on CD4+ T cells. Curr. Opin. Allergy Clin. Immunol. 15, 581–587 (2015)
12. Bacher, P. & Scheffold, A. Flow-cytometric analysis of rare antigen-specific T cells. Cytom. A 83, 692–701 (2013)
13. Bacher, P. & Scheffold, A. New technologies for monitoring human antigen-specific T cells and regulatory T cells by flow-cytometry. Curr. Opin. Pharmacol. 23, 17–24 (2015)
14. Nepom, G. T. MHC class II tetramers. J. Immunol. 188, 2477–2482 (2012)
15. Wambre, E., James, E. A. & Kwok, W. W. Characterization of CD4 + T cell subsets in allergy. Curr. Opin. Immunol. 24, 700–706 (2012)
16. Schulten, V. et al. Previously undescribed grass pollen antigens are the major inducers of T helper 2 cytokine-producing T cells in allergic individuals. Proc. Natl Acad. Sci. USA 110, 3459–3464 (2013)
17. Huang, X. et al. Evolution of the IgE and IgG repertoire to a comprehensive array of allergen molecules in the first decade of life. Allergy 73, 421–430 (2017)
18. Bacher, P. et al. Regulatory T cell specificity directs tolerance versus allergy against aeroantigens in humans. Cell 167, 1067–1078.e16 (2016)
19. Josefowicz, S. Z., Lu, L. F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012)
20. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012)
21. Barzaghi, F., Passerini, L. & Bacchetta, R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front. Immunol. 3, 211 (2012)
22. Bacher, P. et al. Antigen-specific expansion of human regulatory T cells as a major tolerance mechanism against mucosal fungi. Mucosal Immunol. 7, 916–928 (2014)
23. Cebula, A. et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497, 258–262 (2013)
24. Moon, J. J. et al. Quantitative impact of thymic selection on Foxp3 + and Foxp3- subsets of self-peptide/MHC class II-specific CD4 + T cells. Proc. Natl Acad. Sci. USA 108, 14602–14607 (2011)
25. Shafiani, S. et al. Pathogen-specific Treg cells expand early during Mycobacterium tuberculosis infection but are later eliminated in response to interleukin-12. Immunity 38, 1261–1270 (2013)
26. Suffia, I. J., Reckling, S. K., Piccirillo, C. A., Goldszmid, R. S. & Belkaid, Y. Infected site-restricted Foxp3 + natural regulatory T cells are specific for microbial antigens. J. Exp. Med. 203, 777–788 (2006)
27. Lee, H. M., Bautista, J. L., Scott-Browne, J., Mohan, J. F. & Hsieh, C. S. A broad range of self-reactivity drives thymic regulatory T cell selection to limit responses to self. Immunity 37, 475–486 (2012)
28. Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007)
29. Huehn, J. & Beyer, M. Epigenetic and transcriptional control of Foxp3 + regulatory T cells. Semin. Immunol. 27, 10–18 (2015)
30. Huehn, J., Polansky, J. K. & Hamann, A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat. Rev. Immunol. 9, 83–89 (2009)
31. Schmidl, C. et al. The enhancer and promoter landscape of human regulatory and conventional T-cell subpopulations. Blood 123, e68–e78 (2014)
32. Zhang, Y. et al. Genome-wide DNA methylation analysis identifies hypomethylated genes regulated by FOXP3 in human regulatory T cells. Blood 122, 2823–2836 (2013)
33. Geginat, J. et al. The CD4-centered universe of human T cell subsets. Semin. Immunol. 25, 252–262 (2013)
34. Rutz, S. & Ouyang, W. Regulation of interleukin-10 and interleukin-22 expression in T helper cells. Curr. Opin. Immunol. 23, 605–612 (2011)
35. Panduro, M., Benoist, C. & Mathis, D. Tissue Tregs. Annu. Rev. Immunol. 34, 609–633 (2016)
36. Gabrysova, L. & Wraith, D. C. Antigenic strength controls the generation of antigen-specific IL-10-secreting T regulatory cells. Eur. J. Immunol. 40, 1386–1395 (2010)
37. Saraiva, M. et al. Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31, 209–219 (2009)
38. Haringer, B., Lozza, L., Steckel, B. & Geginat, J. Identification and characterization of IL-10/IFN-gamma-producing effector-like T cells with regulatory function in human blood. J. Exp. Med. 206, 1009–1017 (2009)
39. Meiler, F. et al. In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J. Exp. Med. 205, 2887–2898 (2008)
40. Dong, J. et al. IL-10 is excluded from the functional cytokine memory of human CD4+ memory T lymphocytes. J. Immunol. 179, 2389–2396 (2007)
41. Hill, E. V. et al. Glycogen synthase kinase-3 controls IL-10 expression in CD4(+) effector T-cell subsets through epigenetic modification of the IL-10 promoter. Eur. J. Immunol. 45, 1103–1115 (2015)
42. Karwacz, K. et al. Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation. Nat. Immunol. 18, 412–421 (2017)
43. Moffatt, M. F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. 363, 1211–1221 (2010)
44. Engelhardt, K. R. & Grimbacher, B. IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms. Curr. Top. Microbiol. Immunol. 380, 1–18 (2014)
45. Shah, N., Kammermeier, J., Elawad, M. & Glocker, E. O. Interleukin-10 and interleukin-10-receptor defects in inflammatory bowel disease. Curr. Allergy Asthma Rep. 12, 373–379 (2012)
46. Archila, L. D. et al. Ana o 1 and Ana o 2 cashew allergens share cross-reactive CD4(+) T cell epitopes with other tree nuts. Clin. Exp. Allergy 46, 871–883 (2016)
47. Archila, L. D. et al. Grass-specific CD4(+) T-cells exhibit varying degrees of cross-reactivity, implications for allergen-specific immunotherapy. Clin. Exp. Allergy 44, 986–998 (2014)
48. Archila, L. D. et al. Jug r 2-reactive CD4(+) T cells have a dominant immune role in walnut allergy. J. Allergy Clin. Immunol. 136, 983–992.e7 (2015)
49. Renand, A. et al. Chronic cat allergen exposure induces a TH2 cell-dependent IgG4 response related to low sensitization. J. Allergy Clin. Immunol. 136, 1627–1635.e13 (2015)
50. Wambre E. et al. A phenotypically and functionally distinct human TH2 cell subpopulation is associated with allergic disorders. Sci. Transl. Med. 9, eaam9171 (2017)
51. Wambre, E. et al. Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy. J. Allergy Clin. Immunol. 129, 544–551 (2012)
52. Wambre, E. et al. Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner. J. Allergy Clin. Immunol. 133, 872–879.e7 (2014)
53. Anderson, A. E. et al. Seasonal changes in suppressive capacity of CD4+CD25+ T cells from patients with hayfever are allergen-specific and may result in part from expansion of effector T cells among the CD25+ population. Clin. Exp. Allergy 39, 1693–1699 (2009)
54. Bonvalet, M. et al. Allergen-specific CD4+ T cell responses in peripheral blood do not predict the early onset of clinical efficacy during grass pollen sublingual immunotherapy. Clin. Exp. Allergy 42, 1745–1755 (2012)
55. Bonvalet, M. et al. Comparison between major histocompatibility complex class II tetramer staining and surface expression of activation markers for the detection of allergen-specific CD4(+) T cells. Clin. Exp. Allergy 41, 821–829 (2011)
56. Crack, L. R., Chan, H. W., McPherson, T. & Ogg, G. S. Phenotypic analysis of perennial airborne allergen-specific CD4+ T cells in atopic and non-atopic individuals. Clin. Exp. Allergy 41, 1555–1567 (2011)
57. Grindebacke, H., Larsson, P., Wing, K., Rak, S. & Rudin, A. Specific immunotherapy to birch allergen does not enhance suppression of Th2 cells by CD4(+)CD25(+) regulatory T cells during pollen season. J. Clin. Immunol. 29, 752–760 (2009)
58. Haselden, B. M. et al. Proliferation and release of IL-5 and IFN-gamma by peripheral blood mononuclear cells from cat-allergic asthmatics and rhinitics, non-cat-allergic asthmatics, and normal controls to peptides derived from Fel d 1 chain 1. J. Allergy Clin. Immunol. 108, 349–356 (2001)
59. Hinz, D. et al. Lack of allergy to timothy grass pollen is not a passive phenomenon but associated with the allergen-specific modulation of immune reactivity. Clin. Exp. Allergy 46, 705–719 (2016)
60. Kailaanmaki, A. et al. Differential CD4+ T-cell responses of allergic and non-allergic subjects to the immunodominant epitope region of the horse major allergen Equ c 1. Immunology 141, 52–60 (2014)
61. Kinnunen, T. et al. Allergen-specific naive and memory CD4+ T cells exhibit functional and phenotypic differences between individuals with or without allergy. Eur. J. Immunol. 40, 2460–2469 (2010)
62. Ling, E. M. et al. Relation of CD4+CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. Lancet 363, 608–615 (2004)
63. Macaubas, C. et al. Allergen-specific MHC class II tetramer+ cells are detectable in allergic, but not in nonallergic, individuals. J. Immunol. 176, 5069–5077 (2006)
64. Maggi, L. et al. Demonstration of circulating allergen-specific CD4+CD25highFoxp3+ T-regulatory cells in both nonatopic and atopic individuals. J. Allergy Clin. Immunol. 120, 429–436 (2007)
65. Parviainen, S. et al. Comparison of the allergic and nonallergic CD4+ T-cell responses to the major dog allergen Can f 1. J. Allergy Clin. Immunol. 126, 406–408 (2010)
66. Thunberg, S. et al. Immune regulation by CD4+CD25+ T cells and interleukin-10 in birch pollen-allergic patients and non-allergic controls. Clin. Exp. Allergy 37, 1127–1136 (2007)
67. Van Overtvelt, L. et al. Assessment of Bet v 1-specific CD4+ T cell responses in allergic and nonallergic individuals using MHC class II peptide tetramers. J. Immunol. 180, 4514–4522 (2008)
68. Wambre, E. et al. Distinct characteristics of seasonal (Bet v 1) vs. perennial (Der p 1/Der p 2) allergen-specific CD4(+) T cell responses. Clin. Exp. Allergy 41, 192–203 (2011)
69. Wambre, E. et al. Single cell assessment of allergen-specific T cell responses with MHC class II peptide tetramers: methodological aspects. Int. Arch. Allergy Immunol. 146, 99–112 (2008)
70. Tran, D. Q. et al. Selective expression of latency-associated peptide (LAP) and IL-1 receptor type I/II (CD121a/CD121b) on activated human FOXP3+ regulatory T cells allows for their purification from expansion cultures. Blood 113, 5125–5133 (2009)
71. Tran, D. Q., Ramsey, H. & Shevach, E. M. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 110, 2983–2990 (2007)
72. Van Hemelen, D. et al. HLA class II peptide tetramers vs allergen-induced proliferation for identification of allergen-specific CD4 T cells. Allergy 70, 49–58 (2015)
73. Bacher, P. et al. Antigen-reactive T cell enrichment for direct, high-resolution analysis of the human naive and memory Th cell repertoire. J. Immunol. 190, 3967–3976 (2013)
74. Su, L. F., Kidd, B. A., Han, A., Kotzin, J. J. & Davis, M. M. Virus-specific CD4(+) memory-phenotype T cells are abundant in unexposed adults. Immunity 38, 373–383 (2013)
75. Kwok, W. W. et al. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire. J. Immunol. 188, 2537–2544 (2012)
76. Altman, J. D. et al. Phenotypic analysis of antigen-specific T lymphocytes. Science 274, 94–96 (1996)
77. Palomares, O. et al. Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance. J. Allergy Clin. Immunol. 129, 510–520 (2012)
78. Renand, A. et al. Synchronous immune alterations mirror clinical response during allergen immunotherapy. J. Allergy Clin. Immunol. 141, 1750–1760.e1 (2018)
79. Archila, L. L. & Kwok, W. W. Tetramer-guided epitope mapping: a rapid approach to identify HLA-restricted T-cell epitopes from composite allergens. Methods Mol. Biol. 1592, 199–209 (2017)
80. Vaughan, K. et al. Strategies to query and display allergy-derived epitope data from the immune epitope database. Int. Arch. Allergy Immunol. 160, 334–345 (2013)
81. Brosterhus, H. et al. Enrichment and detection of live antigen-specific CD4(+) and CD8(+) T cells based on cytokine secretion. Eur. J. Immunol. 29, 4053–4059 (1999)
82. Akdis, M. 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. 199, 1567–1575 (2004)
83. Schoenbrunn, A. et al. A converse 4-1BB and CD40 ligand expression pattern delineates activated regulatory T cells (Treg) and conventional T cells enabling direct isolation of alloantigen-reactive natural Foxp3+ Treg. J. Immunol. 189, 5985–5994 (2012)
84. Kailaanmaki, A. et al. Human memory CD4+ T cell response to the major dog allergen Can f 5, prostatic kallikrein. Clin. Exp. Allergy 46, 720–729 (2016)
85. Ryan, J. F. et al. Successful immunotherapy induces previously unidentified allergen-specific CD4+ T-cell subsets. Proc. Natl Acad. Sci. USA 113, E1286–1295 (2016)
86. Su, L. F. & Davis, M. M. Antiviral memory phenotype T cells in unexposed adults. Immunol. Rev. 255, 95–109 (2013)
87. Unger, W. W. et al. Early events in peripheral regulatory T cell induction via the nasal mucosa. J. Immunol. 171, 4592–4603 (2003)
88. Boudousquie, C., Pellaton, C., Barbier, N. & Spertini, F. CD4+CD25+ T cell depletion impairs tolerance induction in a murine model of asthma. Clin. Exp. Allergy 39, 1415–1426 (2009)
89. Leech, M. D., Benson, R. A., De Vries, A., Fitch, P. M. & Howie, S. E. Resolution of Der p1-induced allergic airway inflammation is dependent on CD4+CD25+Foxp3+ regulatory cells. J. Immunol. 179, 7050–7058 (2007)
90. Ostroukhova, M. et al. Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta and FOXP3. J. Clin. Invest. 114, 28–38 (2004)
91. Strickland, D. H. et al. Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells. J. Exp. Med. 203, 2649–2660 (2006)
92. Akbari, O. et al. Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergen-induced airway hyperreactivity. Nat. Med. 8, 1024–1032 (2002)
93. Burkhart, C., Liu, G. Y., Anderton, S. M., Metzler, B. & Wraith, D. C. Peptide-induced T cell regulation of experimental autoimmune encephalomyelitis: a role for IL-10. Int. Immunol. 11, 1625–1634 (1999)
94. Duan, W., So, T., Mehta, A. K., Choi, H. & Croft, M. Inducible CD4+LAP+Foxp3- regulatory T cells suppress allergic inflammation. J. Immunol. 187, 6499–6507 (2011)
95. Girtsman, T., Jaffar, Z., Ferrini, M., Shaw, P. & Roberts, K. Natural Foxp3(+) regulatory T cells inhibit Th2 polarization but are biased toward suppression of Th17-driven lung inflammation. J. Leukoc. Biol. 88, 537–546 (2010)
96. Joetham, A. et al. Naturally occurring lung CD4(+)CD25(+) T cell regulation of airway allergic responses depends on IL-10 induction of TGF-beta. J. Immunol. 178, 1433–1442 (2007)
97. Kearley, J., Barker, J. E., Robinson, D. S. & Lloyd, C. M. Resolution of airway inflammation and hyperreactivity after in vivo transfer of CD4+CD25+ regulatory T cells is interleukin 10 dependent. J. Exp. Med. 202, 1539–1547 (2005)
98. Legoux, F. P. et al. CD4+ T cell tolerance to tissue-restricted self antigens is mediated by antigen-specific regulatory T cells rather than deletion. Immunity 43, 896–908 (2015)
99. Jia, Y., Krishnan, L. & Omri, A. Nasal and pulmonary vaccine delivery using particulate carriers. Expert Opin. Drug Deliv. 12, 993–1008 (2015)
100. Sou, T. et al. New developments in dry powder pulmonary vaccine delivery. Trends Biotechnol. 29, 191–198 (2011)
101. Panaccione, D. G. & Coyle, C. M. Abundant respirable ergot alkaloids from the common airborne fungus Aspergillus fumigatus. Appl. Environ. Microbiol. 71, 3106–3111 (2005)
102. Tsukahara, T. Changes in chemical composition of conidia of Aspergillus fumigatus during maturation and germination. Microbiol. Immunol. 24, 747–751 (1980)
103. Platts-Mills, T. A. in Immunology 8th edn (eds. Male, D.K. et al.) 371–393 (Elsevier LTD, Oxford, 2012)
104. Marsh, D. in The Antigens Vol. III (ed. Sela, M) 271–350 (Academic Press, New York, 1975)
105. Rezende, R. M. & Weiner, H. L. History and mechanisms of oral tolerance. Semin. Immunol. 30, 3–11 (2017)
106. Akbari, O., DeKruyff, R. H. & Umetsu, D. T. Pulmonary dendritic cells producing IL-10 mediate tolerance induced by respiratory exposure to antigen. Nat. Immunol. 2, 725–731 (2001)
107. Hoyne, G. F., Askonas, B. A., Hetzel, C., Thomas, W. R. & Lamb, J. R. Regulation of house dust mite responses by intranasally administered peptide: transient activation of CD4 + T cells precedes the development of tolerance in vivo. Int. Immunol. 8, 335–342 (1996)
108. Hoyne, G. F., Jarnicki, A. G., Thomas, W. R. & Lamb, J. R. Characterization of the specificity and duration of T cell tolerance to intranasally administered peptides in mice: a role for intramolecular epitope suppression. Int. Immunol. 9, 1165–1173 (1997)
109. Hoyne, G. F., O’Hehir, R. E., Wraith, D. C., Thomas, W. R. & Lamb, J. R. Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice. J. Exp. Med. 178, 1783–1788 (1993)
110. Sedgwick, J. D. & Holt, P. G. Induction of IgE-isotype specific tolerance by passive antigenic stimulation of the respiratory mucosa. Immunology 50, 625–630 (1983)
111. Sedgwick, J. D. & Holt, P. G. Down-regulation of immune responses to inhaled antigen: studies on the mechanism of induced suppression. Immunology 56, 635–642 (1985)
112. Seymour, B. W., Gershwin, L. J. & Coffman, R. L. Aerosol-induced immunoglobulin (Ig)-E unresponsiveness to ovalbumin does not require CD8 + or T cell receptor (TCR)-gamma/delta + T cells or interferon (IFN)-gamma in a murine model of allergen sensitization. J. Exp. Med. 187, 721–731 (1998)
113. Tsitoura, D. C., DeKruyff, R. H., Lamb, J. R. & Umetsu, D. T. Intranasal exposure to protein antigen induces immunological tolerance mediated by functionally disabled CD4 + T cells. J. Immunol. 163, 2592–2600 (1999)
114. Duan, W. & Croft, M. Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells. Ann. Am. Thorac. Soc. 11(Suppl 5), S306–S313 (2014)
115. Hammad, H. & Lambrecht, B. N. Dendritic cells and airway epithelial cells at the interface between innate and adaptive immune responses. Allergy 66, 579–587 (2011)
116. Kwok, W. W. et al. Direct ex vivo analysis of allergen-specific CD4 + T cells. J. Allergy Clin. Immunol. 125, 1407–1409.e01 (2010)
117. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001)
118. Russell, R. J. & Brightling, C. Pathogenesis of asthma: implications for precision medicine. Clin. Sci. (Lond.) 131, 1723–1735 (2017)
119. Jin, H. S., Park, Y., Elly, C. & Liu, Y. C. Itch expression by Treg cells controls Th2 inflammatory responses. J. Clin. Invest. 123, 4923–4934 (2013)
120. Ulges, A. et al. Protein kinase CK2 enables regulatory T cells to suppress excessive TH2 responses in vivo. Nat. Immunol. 16, 267–275 (2015)
121. Wan, Y. Y. & Flavell, R. A. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445, 766–770 (2007)
122. Wang, Y., Souabni, A., Flavell, R. A. & Wan, Y. Y. An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo. J. Immunol. 185, 5983–5992 (2010)
123. Hansmann, L. et al. Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression. J. Immunol. 188, 1275–1282 (2012)
124. Geraldes, L. et al. Expression patterns of HLA-DR + or HLA-DR- on CD4 + /CD25 + + /CD127low regulatory T cells in patients with allergy. J. Investig. Allergol. Clin. Immunol. 20, 201–209 (2010)
125. Grindebacke, H. et al. Defective suppression of Th2 cytokines by CD4CD25 regulatory T cells in birch allergics during birch pollen season. Clin. Exp. Allergy 34, 1364–1372 (2004)
126. Provoost, S. et al. Decreased FOXP3 protein expression in patients with asthma. Allergy 64, 1539–1546 (2009)
127. Shi, H. Z. et al. Regulatory CD4 + CD25 + T lymphocytes in peripheral blood from patients with atopic asthma. Clin. Immunol. 113, 172–178 (2004)
128. Wang, L. H., Lin, Y. H., Yang, J. & Guo, W. Insufficient increment of CD4 + CD25 + regulatory T cells after stimulation in vitro with allergen in allergic asthma. Int. Arch. Allergy Immunol. 148, 199–210 (2009)
129. Xu, G. et al. A possible role of CD4 + CD25 + T cells as well as transcription factor Foxp3 in the dysregulation of allergic rhinitis. Laryngoscope 117, 876–880 (2007)
130. Hartl, D. et al. Quantitative and functional impairment of pulmonary CD4 + CD25hi regulatory T cells in pediatric asthma. J. Allergy Clin. Immunol. 119, 1258–1266 (2007)
131. Heier, I. et al. Bronchial response pattern of antigen presenting cells and regulatory T cells in children less than 2 years of age. Thorax 63, 703–709 (2008)
132. Lee, J. H. et al. The levels of CD4 + CD25 + regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma. Clin. Exp. Immunol. 148, 53–63 (2007)
133. Lin, Y. L., Shieh, C. C. & Wang, J. Y. The functional insufficiency of human CD4 + CD25 high T-regulatory cells in allergic asthma is subjected to TNF-alpha modulation. Allergy 63, 67–74 (2008)
134. Meszaros, G. et al. FoxP3 + regulatory T cells in childhood allergic rhinitis and asthma. J. Investig. Allergol. Clin. Immunol. 19, 238–240 (2009)
135. Stelmaszczyk-Emmel, A., Zawadzka-Krajewska, A., Szypowska, A., Kulus, M. & Demkow, U. Frequency and activation of CD4 + CD25 FoxP3 + regulatory T cells in peripheral blood from children with atopic allergy. Int. Arch. Allergy Immunol. 162, 16–24 (2013)
136. Santegoets, S. J. et al. Monitoring regulatory T cells in clinical samples: consensus on an essential marker set and gating strategy for regulatory T cell analysis by flow cytometry. Cancer Immunol. Immunother. 64, 1271–1286 (2015)
137. Bellinghausen, I., Klostermann, B., Knop, J. & Saloga, J. Human CD4 + CD25 + T cells derived from the majority of atopic donors are able to suppress TH1 and TH2 cytokine production. J. Allergy Clin. Immunol. 111, 862–868 (2003)
138. Lewkowich, I. P. et al. CD4 + CD25 + T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function. J. Exp. Med. 202, 1549–1561 (2005)
139. Jaffar, Z., Sivakuru, T. & Roberts, K. CD4 + CD25 + T cells regulate airway eosinophilic inflammation by modulating the Th2 cell phenotype. J. Immunol. 172, 3842–3849 (2004)
140. Hadeiba, H. & Locksley, R. M. Lung CD25 CD4 regulatory T cells suppress type 2 immune responses but not bronchial hyperreactivity. J. Immunol. 170, 5502–5510 (2003)
141. Dehzad, N. et al. Regulatory T cells more effectively suppress Th1-induced airway inflammation compared with Th2. J. Immunol. 186, 2238–2244 (2011)
142. Cosmi, L. et al. Th2 cells are less susceptible than Th1 cells to the suppressive activity of CD25 + regulatory thymocytes because of their responsiveness to different cytokines. Blood 103, 3117–3121 (2004)
143. Stassen, M. et al. Differential regulatory capacity of CD25 + T regulatory cells and preactivated CD25 + T regulatory cells on development, functional activation, and proliferation of Th2 cells. J. Immunol. 173, 267–274 (2004)
144. Bopp, T. et al. Inhibition of cAMP degradation improves regulatory T cell-mediated suppression. J. Immunol. 182, 4017–4024 (2009)
145. Huang, H., Ma, Y., Dawicki, W., Zhang, X. & Gordon, J. R. Comparison of induced versus natural regulatory T cells of the same TCR specificity for induction of tolerance to an environmental antigen. J. Immunol. 191, 1136–1143 (2013)
146. Kearley, J., Robinson, D. S. & Lloyd, C. M. CD4 + CD25 + regulatory T cells reverse established allergic airway inflammation and prevent airway remodeling. J. Allergy Clin. Immunol. 122, 617–624.e6 (2008)
147. Saito, K. et al. Differential regulatory function of resting and preactivated allergen-specific CD4 + CD25 + regulatory T cells in Th2-type airway inflammation. J. Immunol. 181, 6889–6897 (2008)
148. Bateman, E. A., Ardern-Jones, M. R. & Ogg, G. S. Persistent central memory phenotype of circulating Fel d 1 peptide/DRB1*0101 tetramer-binding CD4 + T cells. J. Allergy Clin. Immunol. 118, 1350–1356 (2006)
149. Skrindo, I., Farkas, L., Kvale, E. O., Johansen, F. E. & Jahnsen, F. L. Depletion of CD4 + CD25 + CD127lo regulatory T cells does not increase allergen-driven T cell activation. Clin. Exp. Allergy 38, 1752–1759 (2008)
150. Gollwitzer, E. S. et al. Lung microbiota promotes tolerance to allergens in neonates via PD-L1. Nat. Med. 20, 642–647 (2014)
151. Lloyd, C. M. & Marsland, B. J. Lung homeostasis: influence of age, microbes, and the immune system. Immunity 46, 549–561 (2017)
152. Nouri-Aria, K. T. et al. Grass pollen immunotherapy induces mucosal and peripheral IL-10 responses and blocking IgG activity. J. Immunol. 172, 3252–3259 (2004)
153. Akdis, C. A., Blesken, T., Akdis, M., Wuthrich, B. & Blaser, K. Role of interleukin 10 in specific immunotherapy. J. Clin. Invest. 102, 98–106 (1998)
154. Bohle, B. et al. Sublingual immunotherapy induces IL-10-producing T regulatory cells, allergen-specific T-cell tolerance, and immune deviation. J. Allergy Clin. Immunol. 120, 707–713 (2007)
155. Cosmi, L. et al. Sublingual immunotherapy with Dermatophagoides monomeric allergoid down-regulates allergen-specific immunoglobulin E and increases both interferon-gamma- and interleukin-10-production. Clin. Exp. Allergy 36, 261–272 (2006)
156. Francis, J. N. et al. Grass pollen immunotherapy: IL-10 induction and suppression of late responses precedes IgG4 inhibitory antibody activity. J. Allergy Clin. Immunol. 121, 1120–1125 e1122 (2008)
157. Francis, J. N., Till, S. J. & Durham, S. R. Induction of IL-10 + CD4 + CD25 + T cells by grass pollen immunotherapy. J. Allergy Clin. Immunol. 111, 1255–1261 (2003)
158. Jutel, M. et al. IL-10 and TGF-beta cooperate in the regulatory T cell response to mucosal allergens in normal immunity and specific immunotherapy. Eur. J. Immunol. 33, 1205–1214 (2003)
159. Lou, W., Wang, C., Wang, Y., Han, D. & Zhang, L. Responses of CD4(+) CD25(+) Foxp3(+) and IL-10-secreting type I T regulatory cells to cluster-specific immunotherapy for allergic rhinitis in children. Pediatr. Allergy Immunol. 23, 140–149 (2012)
160. Mobs, C. et al. Birch pollen immunotherapy results in long-term loss of Bet v 1-specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies. J. Allergy Clin. Immunol. 130, 1108–1116.e06 (2012)
161. Mobs, C. et al. Birch pollen immunotherapy leads to differential induction of regulatory T cells and delayed helper T cell immune deviation. J. Immunol. 184, 2194–2203 (2010)
162. O’Hehir, R. E. et al. House dust mite sublingual immunotherapy: the role for transforming growth factor-beta and functional regulatory T cells. Am. J. Respir. Crit. Care Med. 180, 936–947 (2009)
163. Schulten, V. et al. Distinct modulation of allergic T cell responses by subcutaneous vs. sublingual allergen-specific immunotherapy. Clin. Exp. Allergy 46, 439–448 (2016)
164. Reefer, A. J. et al. A role for IL-10-mediated HLA-DR7-restricted T cell-dependent events in development of the modified Th2 response to cat allergen. J. Immunol. 172, 2763–2772 (2004)
165. Durham, S. R. et al. Long-term clinical efficacy in grass pollen-induced rhinoconjunctivitis after treatment with SQ-standardized grass allergy immunotherapy tablet. J. Allergy Clin. Immunol. 125, 131–138 (2010). e131–e137
166. Durham, S. R. et al. Long-term clinical efficacy of grass-pollen immunotherapy. N. Engl. J. Med. 341, 468–475 (1999)
167. Erekosima, N. et al. Effectiveness of subcutaneous immunotherapy for allergic rhinoconjunctivitis and asthma: a systematic review. Laryngoscope 124, 616–627 (2014)
168. Jacobsen, L. et al. Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study. Allergy 62, 943–948 (2007)
169. Moller, C. et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J. Allergy Clin. Immunol. 109, 251–256 (2002)
170. Niggemann, B. et al. Five-year follow-up on the PAT study: specific immunotherapy and long-term prevention of asthma in children. Allergy 61, 855–859 (2006)
171. Ali, F. R., Oldfield, W. L., Higashi, N., Larche, M. & Kay, A. B. Late asthmatic reactions induced by inhalation of allergen-derived T cell peptides. Am. J. Respir. Crit. Care Med. 169, 20–26 (2004)
172. Keles, S. et al. A novel approach in allergen-specific immunotherapy: combination of sublingual and subcutaneous routes. J. Allergy Clin. Immunol. 128, 808.e7–815.e7 (2011)
173. Benjaponpitak, S. et al. The kinetics of change in cytokine production by CD4 T cells during conventional allergen immunotherapy. J. Allergy Clin. Immunol. 103(3 Pt 1), 468–475 (1999)
174. Ebner, C. et al. Immunological changes during specific immunotherapy of grass pollen allergy: reduced lymphoproliferative responses to allergen and shift from TH2 to TH1 in T-cell clones specific for Phl p 1, a major grass pollen allergen. Clin. Exp. Allergy 27, 1007–1015 (1997)
175. Wachholz, P. A. et al. Grass pollen immunotherapy for hayfever is associated with increases in local nasal but not peripheral Th1:Th2 cytokine ratios. Immunology 105, 56–62 (2002)
176. Gardner, L. M., O’Hehir, R. E. & Rolland, J. M. High dose allergen stimulation of T cells from house dust mite-allergic subjects induces expansion of IFN-gamma + T cells, apoptosis of CD4 + IL-4 + T cells and T cell anergy. Int. Arch. Allergy Immunol. 133, 1–13 (2004)
177. Secrist, H., Chelen, C. J., Wen, Y., Marshall, J. D. & Umetsu, D. T. Allergen immunotherapy decreases interleukin 4 production in CD4 + T cells from allergic individuals. J. Exp. Med. 178, 2123–2130 (1993)
178. Aslam, A., Chan, H., Warrell, D. A., Misbah, S. & Ogg, G. S. Tracking antigen-specific T-cells during clinical tolerance induction in humans. PLoS ONE 5, e11028 (2010)
179. Yamanaka, K. et al. Induction of IL-10-producing regulatory T cells with TCR diversity by epitope-specific immunotherapy in pollinosis. J. Allergy Clin. Immunol. 124, 842.e7–845.e7 (2009)
180. Campbell, J. D. et al. Peptide immunotherapy in allergic asthma generates IL-10-dependent immunological tolerance associated with linked epitope suppression. J. Exp. Med. 206, 1535–1547 (2009)
181. Kerstan, A., Beyersdorf, N., Stoevesandt, J. & Trautmann, A. Wasp venom immunotherapy expands a subpopulation of CD4(+)CD25 + forkhead box protein 3-positive regulatory T cells expressing the T-cell receptor Vbeta2 and Vbeta5.1 chains. J. Allergy Clin. Immunol. 130, 994.e3–996.e3 (2012)
182. Pereira-Santos, M. C. et al. Expansion of circulating Foxp3 + D25bright CD4 + T cells during specific venom immunotherapy. Clin. Exp. Allergy 38, 291–297 (2008)
183. Swamy, R. S. et al. Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy. J. Allergy Clin. Immunol. 130, 215.e7–224.e7 (2012)
184. Syed, A. 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. 133, 500–510 (2014)
185. Radulovic, S., Jacobson, M. R., Durham, S. R. & Nouri-Aria, K. T. Grass pollen immunotherapy induces Foxp3-expressing CD4 + CD25 + cells in the nasal mucosa. J. Allergy Clin. Immunol. 121, 1467–1472, 1472.e1 (2008)
186. Skrindo, I., Scheel, C., Johansen, F. E. & Jahnsen, F. L. Experimentally induced accumulation of Foxp3(+) T cells in upper airway allergy. Clin. Exp. Allergy 41, 954–962 (2011)
187. Bohm, L. et al. IL-10 and regulatory T cells cooperate in allergen-specific immunotherapy to ameliorate allergic asthma. J. Immunol. 194, 887–897 (2015)
188. Maazi, H. et al. Contribution of regulatory T cells to alleviation of experimental allergic asthma after specific immunotherapy. Clin. Exp. Allergy 42, 1519–1528 (2012)