The deviated balance between regulatory T cell and Th17 in autoimmunity

Immunopharmacology and Immunotoxicology

Volumn 34, Issue 5, 2012, Pages 727-739

  Jadidi Niaragh, Farhad ^a   Mirshafiey, Abbas ^a  

^a TEHRAN UNIVERSITY OF MEDICAL SCIENCES   (Iran)

Author keywords

Autoimmunity; Multiple sclerosis; Regulatory T cell; Rheumatoid arthritis; Th17

Indexed keywords

RETINOIC ACID; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA;

AUTOIMMUNE DISEASE; AUTOIMMUNITY; CD8+ T LYMPHOCYTE; CELL DIFFERENTIATION; CELL EXPANSION; CELL INTERACTION; HUMAN; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; TH17 CELL; TH3 CELL;

ANIMALS; AUTOIMMUNE DISEASES; AUTOIMMUNITY; HUMANS; T-LYMPHOCYTES, REGULATORY; TH17 CELLS;

EID: 84866252774     PISSN: 08923973     EISSN: 15322513     Source Type: Journal    
DOI: 10.3109/08923973.2011.619987     Document Type: Review

References (122)

1. Murphy, K.M., Reiner, S.L. The lineage decisions of helper T cells. Nat Rev Immunol 2002, 2, 933-944
2. Abbas, A.K., Murphy, K.M., Sher, A. Functional diversity of helper T lymphocytes. Nature 1996, 383, 787-793
3. Gershon, R.K., Kondo, K. Cell interactions in the induction of tolerance: The role of thymic lymphocytes. Immunology 1970, 18, 723-737
4. 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 echanism of self-tolerance causes various autoimmune diseases. J Immunol 1995, 155, 1151-1164
5. Jonuleit, H., Schmitt, E. The regulatory T cell family: Distinct subsets and their interrelations. J Immunol 2003, 171, 6323-6327
6. Vignali, D.A., Collison, L.W., Workman, C.J. How regulatory T cells work. Nat Rev Immunol 2008, 8, 523-532
7. Vignali, D. How many mechanisms do regulatory T cells need? Eur J Immunol 2008, 38, 908-911
8. Chen, Z., O'Shea, J.J. Th17 cells: A new fate for differentiating helper T cells. Immunol Res 2008, 41, 87-102
9. Jäger, A., Kuchroo, V.K. Effector and regulatory T-cell subsets in autoimmunity and tissue inflammation. Scand J Immunol 2010, 72, 173-184
10. Nowak, E.C., Noelle, R.J. Interleukin-9 and T cell subsets. Cell Cycle 2009, 8, 3798-3799
11. Okada, R., Kondo, T., Matsuki, F., Takata, H., Takiguchi, M. Phenotypic classification of human CD4+ T cell subsets and their differentiation. Int Immunol 2008, 20, 1189-1199
12. Rolf, J., Fairfax, K., Turner, M. Signaling pathways in T follicular helper cells. J Immunol 2010, 184, 6563-6568
13. Laurent, C., Fazilleau, N., Brousset, P. A novel subset of T-helper cells: Follicular T-helper cells and their markers. Haematologica 2010, 95, 356-358
14. Long, M., Park, S.G., Strickland, I., Hayden, M.S., Ghosh, S. Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 2009, 31, 921-931
15. Hori, S. c-Rel: A pioneer in directing regulatory T cell lineage commitment? Eur J Immunol 2010,40, 664-667
16. Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X.P., Forbush, K., Rudensky, A.Y. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010, 463, 808-812
17. Fontenot, J.D., Gavin, M.A., Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003, 4, 330-336
18. Gavin, M.A., Rasmussen, J.P., Fontenot, J.D., Vasta, V., Manganiello, V.C., Beavo, J.A., Rudensky, A.Y. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007, 445, 771-775
19. Roncarolo, M.G., Gregori, S. Is FOXP3 a bona fide marker for human regulatory T cells? Eur J Immunol 2008, 38, 925-927
20. Liu, W., Putnam, A.L., Xu-Yu, Z., Szot, G.L., Lee, M.R., Zhu, S., Gottlieb, P.A., Kapranov, P., Gingeras, T.R., Fazekas de St Groth, B., Clayberger, C., Soper, D.M., Ziegler, S.F., Bluestone, J.A. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006, 203, 1701-1711
21. Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and nonself. Nat Immunol 2005, 6, 345-352
22. Sakaguchi, S., Miyara, M., Costantino, C.M., Hafler, D.A. FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 2010, 10, 490-500
23. Shevach, E.M. CD4+ CD25+ suppressor T cells: More questions than answers. Nat Rev Immunol 2002, 2, 389-400
24. Feger, U., Tolosa, E., Huang, Y.H., Waschbisch, A., Biedermann, T., Melms, A., Wiendl, H. HLA-G expression defines a novel regulatory T-cell subset present in human peripheral blood and sites of inflammation. Blood 2007, 110, 568-577
25. Wiendl, H., Feger, U., Mittelbronn, M., Jack, C., Schreiner, B., Stadelmann, C., Antel, J., Brueck, W., Meyermann, R., Bar-Or, A., Kieseier, B.C., Weller, M. Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: Implications for CNS immunity. Brain 2005, 128, 2689-2704
26. Bacchetta, R., Sartirana, C., Levings, M.K., Bordignon, C., Narula, S., Roncarolo, M.G. Growth and expansion of human T regulatory type 1 cells are independent from TCR activation but require exogenous cytokines. Eur J Immunol 2002, 32, 2237-2245
27. Roncarolo, M.G., Gregori, S., Battaglia, M., Bacchetta, R., Fleischhauer, K., Levings, M.K. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev 2006, 212, 28-50
28. Roncarolo, M.G., Bacchetta, R., Bordignon, C., Narula, S., Levings, M.K. Type 1 T regulatory cells. Immunol Rev 2001, 182, 68-79
29. Levings, M.K., Sangregorio, R., Galbiati, F., Squadrone, S., de Waal Malefyt, R., Roncarolo, M.G. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001, 166, 5530-5539
30. Weiner, H.L. Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 2001, 182, 207-214
31. Fukaura, H., Kent, S.C., Pietrusewicz, M.J., Khoury, S.J., Weiner, H.L., Hafler, D.A. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factorbeta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest 1996, 98, 70-77
32. Faria, A.M., Weiner, H.L. Oral tolerance. Immunol Rev 2005, 206, 232-259
33. Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T.W., Sakaguchi, S. Immunologic selftolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000, 192, 303-310
34. Carrier, Y., Yuan, J., Kuchroo, V.K., Weiner, H.L. Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice. J Immunol 2007, 178, 179-185
35. Filaci, G., Fenoglio, D., Fravega, M., Ansaldo, G., Borgonovo, G., Traverso, P., Villaggio, B., Ferrera, A., Kunkl, A., Rizzi, M., Ferrera, F., Balestra, P., Ghio, M., Contini, P., Setti, M., Olive, D., Azzarone, B., Carmignani, G., Ravetti, J.L., Torre, G., Indiveri, F. CD8+ CD28-T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J Immunol 2007, 179, 4323-4334
36. Kiniwa, Y., Miyahara, Y., Wang, H.Y., Peng, W., Peng, G., Wheeler, T.M., Thompson, T.C., Old, L.J., Wang, R.F. CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer. Clin Cancer Res 2007, 13, 6947-6958
37. Cosmi, L., Liotta, F., Lazzeri, E., Francalanci, M., Angeli, R., Mazzinghi, B., Santarlasci, V., Manetti, R., Vanini, V., Romagnani, P., Maggi, E., Romagnani, S., Annunziato, F. Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood 2003, 102, 4107-4114
38. Smith, T.R., Kumar, V. Revival of CD8+ Treg-mediated suppression. Trends Immunol 2008, 29, 337-342
39. Xystrakis, E., Dejean, A.S., Bernard, I., Druet, P., Liblau, R., Gonzalez-Dunia, D., Saoudi, A. Identification of a novel natural regulatory CD8 T-cell subset and analysis of its mechanism of regulation. Blood 2004, 104, 3294-3301
40. Bettelli, E., Korn, T., Kuchroo, V.K. Th17: The third member of the effector T cell trilogy. Curr Opin Immunol 2007, 19, 652-657
41. Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M., Murphy, K.M. Th17: An effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006, 24, 677-688
42. Kawaguchi, M., Adachi, M., Oda, N., Kokubu, F., Huang, S.K. IL-17 cytokine family. J Allergy Clin Immunol 2004, 114, 1265-73; quiz 1274
43. Kolls, J.K., Lindén, A. Interleukin-17 family members and inflammation. Immunity 2004, 21, 467-476
44. Jadidi-Niaragh, F., Mirshafiey, A. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 2011, 74, 1-13
45. Acosta-Rodriguez, E.V., Rivino, L., Geginat, J., Jarrossay, D., Gattorno, M., Lanzavecchia, A., Sallusto, F., Napolitani, G. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 2007, 8, 639-646
46. Annunziato, F., Cosmi, L., Santarlasci, V., Maggi, L., Liotta, F., Mazzinghi, B., Parente, E., Filì, L., Ferri, S., Frosali, F., Giudici, F., Romagnani, P., Parronchi, P., Tonelli, F., Maggi, E., Romagnani, S. Phenotypic and functional features of human Th17 cells. J Exp Med 2007, 204, 1849-1861
47. Annunziato, F., Cosmi, L., Liotta, F., Maggi, E., Romagnani, S. The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation. Int Immunol 2008, 20, 1361-1368
48. Das, J., Ren, G., Zhang, L., Roberts, A.I., Zhao, X., Bothwell, A.L., Van Kaer, L., Shi, Y., Das, G. Transforming growth factor beta is dispensable for the molecular orchestration of Th17 cell differentiation. J Exp Med 2009, 206, 2407-2416
49. Ghoreschi, K., Laurence, A., Yang, X.P., Tato, C.M., McGeachy, M.J., Konkel, J.E., Ramos, H.L., Wei, L., Davidson, T.S., Bouladoux, N., Grainger, J.R., Chen, Q., Kanno, Y., Watford, W.T., Sun, H.W., Eberl, G., Shevach, E.M., Belkaid, Y., Cua, D.J., Chen, W., O'Shea, J.J. Generation of pathogenic T(H)17 cells in the absence of TGF-ß signalling. Nature 2010, 467, 967-971
50. Korn, T., Bettelli, E., Gao, W., Awasthi, A., Jäger, A., Strom, T.B., Oukka, M., Kuchroo, V.K. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007, 448, 484-487
51. Nurieva, R., Yang, X.O., Martinez, G., Zhang, Y., Panopoulos, A.D., Ma, L., Schluns, K., Tian, Q., Watowich, S.S., Jetten, A.M., Dong, C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007, 448, 480-483
52. Zhou, L., Ivanov, I.I., Spolski, R., Min, R., Shenderov, K., Egawa, T., Levy, D.E., Leonard, W.J., Littman, D.R. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007, 8, 967-974
53. Wei, L., Laurence, A., Elias, K.M., O'Shea, J.J. IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 2007, 282, 34605-34610
54. Unutmas, D. RORC2: The master of human Th17 cell programming. Eur J Immunol 2009, 39, 1452-1455
55. Ivanov, I.I., McKenzie, B.S., Zhou, L., Tadokoro, C.E., Lepelley, A., Lafaille, J.J., Cua, D.J., Littman, D.R. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006, 126, 1121-1133
56. Yang, X.O., Panopoulos, A.D., Nurieva, R., Chang, S.H., Wang, D., Watowich, S.S., Dong, C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 2007, 282, 9358-9363
57. Kimura, A., Naka, T., Nohara, K., Fujii-Kuriyama, Y., Kishimoto, T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci USA 2008, 105, 9721-9726
58. Brüstle, A., Heink, S., Huber, M., Rosenplänter, C., Stadelmann, C., Yu, P., Arpaia, E., Mak, T.W., Kamradt, T., Lohoff, M. The development of inflammatory T(H)-17 cells requires interferonregulatory factor 4. Nat Immunol 2007, 8, 958-966
59. Hirota, K., Martin, B., Veldhoen, M. Development, regulation and functional capacities of Th17 cells. Semin Immunopathol 2010, 32, 3-16
60. Li, M.O., Wan, Y.Y., Flavell, R.A. T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1-and Th17-cell differentiation. Immunity 2007, 26, 579-591
61. Niu, Q., Huang, Z.C., Cai, B., Wang, L.L., Feng, W.H. [Study on ratio imbalance of peripheral blood Th17/Treg cells in patients with rheumatoid arthritis]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2010, 26, 267-9, 272
62. Hofstetter, H., Gold, R., Hartung, H.P. Th17 Cells in MS and Experimental Autoimmune Encephalomyelitis. Int MS J 2009, 16, 12-18
63. Brucklacher-Waldert, V., Stuerner, K., Kolster, M., Wolthausen, J., Tolosa, E. Phenotypical and functional characterization of T helper 17 cells in multiple sclerosis. Brain 2009, 132, 3329-3341
64. O'Connor, R.A., Anderton, S.M. Foxp3+ regulatory T cells in the control of experimental CNS autoimmune disease. J Neuroimmunol 2008, 193, 1-11
65. Tennakoon, D.K., Mehta, R.S., Ortega, S.B., Bhoj, V., Racke, M.K., Karandikar, N.J. Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. J Immunol 2006, 176, 7119-7129
66. Vandenbark, A.A., Huan, J., Agotsch, M., La Tocha, D., Goelz, S., Offner, H., Lanker, S., Bourdette, D. Interferon-beta-1a treatment increases CD56bright natural killer cells and CD4+CD25+ Foxp3 expression in subjects with multiple sclerosis. J Neuroimmunol 2009, 215, 125-128
67. Olivito, B., Simonini, G., Ciullini, S., Moriondo, M., Betti, L., Gambineri, E., Cantarini, L., De Martino, M., Azzari, C., Cimaz, R. Th17 transcription factor RORC2 is inversely correlated with FOXP3 expression in the joints of children with juvenile idiopathic arthritis. J Rheumatol 2009, 36, 2017-2024
68. Feger, U., Luther, C., Poeschel, S., Melms, A., Tolosa, E., Wiendl, H. Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol 2007, 147, 412-418
69. Haas, J., Hug, A., Viehöver, A., Fritzsching, B., Falk, C.S., Filser, A., Vetter, T., Milkova, L., Korporal, M., Fritz, B., Storch-Hagenlocher, B., Krammer, P.H., Suri-Payer, E., Wildemann, B. Reduced suppressive effect of CD4+CD25high regulatory T cells on the T cell immune response against myelin oligodendrocyte lycoprotein in patients with multiple sclerosis. Eur J Immunol 2005, 35, 3343-3352
70. Saresella, M., Marventano, I., Longhi, R., Lissoni, F., Trabattoni, D., Mendozzi, L., Caputo, D., Clerici, M. CD4+CD25+FoxP3+PD1-regulatory T cells in acute and stable relapsing-remitting multiple sclerosis and their modulation by therapy. FASEB J 2008, 22, 3500-3508
71. Jadidi-Niaragh, F., Mirshafiey, A. Regulatory T-cell as orchestra leader in immunosuppression process of multiple sclerosis. Immunopharmacol Immunotoxicol 2011, 33, 545-567
72. Valmori, D., Raffin, C., Raimbaud, I., Ayyoub, M. Human ROR?t+ TH17 cells preferentially differentiate from naive FOXP3+Treg in the presence of lineage-specific polarizing factors. Proc Natl Acad Sci USA 2010, 107, 19402-19407
73. Tartar, D.M., VanMorlan, A.M., Wan, X., Guloglu, F.B., Jain, R., Haymaker, C.L., Ellis, J.S., Hoeman, C.M., Cascio, J.A., Dhakal, M., Oukka, M., Zaghouani, H. FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes. J Immunol 2010, 184, 3377-3385
74. Hatton, R.D., Weaver, C.T. Duality in the Th17-Treg developmental decision. F1000 Biol Rep 2009, 1, 5
75. Yang, X.O., Nurieva, R., Martinez, G.J., Kang, H.S., Chung, Y., Pappu, B.P., Shah, B., Chang, S.H., Schluns, K.S., Watowich, S.S., Feng, X.H., Jetten, A.M., Dong, C. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008, 29, 44-56
76. Zhou, L., Lopes, J.E., Chong, M.M., Ivanov, I.I., Min, R., Victora, G.D., Shen, Y., Du, J., Rubtsov, Y.P., Rudensky, A.Y., Ziegler, S.F., Littman, D.R. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008, 453, 236-240
77. Chen, Z., Laurence, A., O'Shea, J.J. Signal transduction pathways and transcriptional regulation in the control of Th17 differentiation. Semin Immunol 2007, 19, 400-408
78. Xu, L., Kitani, A., Fuss, I., Strober, W. Cutting edge: Regulatory T cells induce CD4+CD25-Foxp3-T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 2007, 178, 6725-6729
79. Dardalhon, V., Awasthi, A., Kwon, H., Galileos, G., Gao, W., Sobel, R.A., Mitsdoerffer, M., Strom, T.B., Elyaman, W., Ho, I.C., Khoury, S., Oukka, M., Kuchroo, V.K. IL-4 inhibits TGF-betainduced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 2008, 9, 1347-1355
80. Elyaman, W., Bradshaw, E.M., Uyttenhove, C., Dardalhon, V., Awasthi, A., Imitola, J., Bettelli, E., Oukka, M., van Snick, J., Renauld, J.C., Kuchroo, V.K., Khoury, S.J. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci USA 2009, 106, 12885-12890
81. Locksley, R.M. Nine lives: Plasticity among T helper cell subsets. J Exp Med 2009, 206, 1643-1646
82. Wan, Y.Y., Flavell, R.A. TGF-beta and regulatory T cell in immunity and autoimmunity. J Clin Immunol 2008, 28, 647-659
83. Mirshafiey, A., Mohsenzadegan, M. TGF-beta as a promising option in the treatment of multiple sclerosis. Neuropharmacology 2009, 56, 929-936
84. Jadidi-Niaragh, F., Mirshafiey, A. Histamine and histamine receptors in pathogenesis and treatment of multiple sclerosis. Neuropharmacology 2010, 59, 180-189
85. Lu, L., Wang, J., Zhang, F., Chai, Y., Brand, D., Wang, X., Horwitz, D.A., Shi, W., Zheng, S.G. Role of SMAD and non-SMAD signals in the development of Th17 and regulatory T cells. J Immunol 2010, 184, 4295-4306
86. Maitra, U., Davis, S., Reilly, C.M., Li, L. Differential regulation of Foxp3 and IL-17 expression in CD4 T helper cells by IRAK-1. J Immunol 2009, 182, 5763-5769
87. Mucida, D., Park, Y., Kim, G., Turovskaya, O., Scott, I., Kronenberg, M., Cheroutre, H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007, 317, 256-260
88. Chen, Z., Tato, C.M., Muul, L., Laurence, A., O'Shea, J.J. Distinct regulation of interleukin-17 in human T helper lymphocytes. Arthritis Rheum 2007, 56, 2936-2946
89. Aukrust, P., Müller, F., Ueland, T., Svardal, A.M., Berge, R.K., Frøland, S.S. Decreased vitamin A levels in common variable immunodeficiency: Vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses. Eur J Clin Invest 2000, 30, 252-259
90. Kinoshita, K., Yoo, B.S., Nozaki, Y., Sugiyama, M., Ikoma, S., Ohno, M., Funauchi, M., Kanamaru, A. Retinoic acid reduces autoimmune renal injury and increases survival in NZB/W F1 mice. J Immunol 2003, 170, 5793-5798
91. Bai, A., Lu, N., Guo, Y., Liu, Z., Chen, J., Peng, Z. All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis. J Leukoc Biol 2009, 86, 959-969
92. Klemann, C., Raveney, B.J., Klemann, A.K., Ozawa, T., von Hörsten, S., Shudo, K., Oki, S., Yamamura, T. Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis. Am J Pathol 2009, 174, 2234-2245
93. Van, Y.H., Lee, W.H., Ortiz, S., Lee, M.H., Qin, H.J., Liu, C.P. All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells ithout affecting Th17 cells. Diabetes 2009, 58, 146-155
94. van den Brandt, J., Fischer, H.J., Walter, L., Hünig, T., Klöting, I., Reichardt, H.M. Type 1 diabetes in BioBreeding rats is critically linked to an imbalance between Th17 and regulatory T cells and an altered TCR repertoire. J Immunol 2010, 185, 2285-2294
95. Lundsgaard, D., Holm, T.L., Hornum, L., Markholst, H. In vivo control of diabetogenic T-cells by regulatory CD4+CD25+ T-cells expressing Foxp3. Diabetes 2005, 54, 1040-1047
96. Poussier, P., Ning, T., Murphy, T., Dabrowski, D., Ramanathan, S. Impaired post-thymic development of regulatory CD4 + 25+ T cells contributes to diabetes pathogenesis in BB rats. J Immunol 2005, 174, 4081-4089
97. Honkanen, J., Nieminen, J.K., Gao, R., Luopajarvi, K., Salo, H.M., Ilonen, J., Knip, M., Otonkoski, T., Vaarala, O. IL-17 immunity in human type 1 diabetes. J Immunol 2010, 185, 1959-1967
98. Xiao, S., Jin, H., Korn, T., Liu, S.M., Oukka, M., Lim, B., Kuchroo, V.K. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-betadriven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 2008, 181, 2277-2284
99. Elias, K.M., Laurence, A., Davidson, T.S., Stephens, G., Kanno, Y., Shevach, E.M., O'Shea, J.J. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 2008, 111, 1013-1020
100. Schambach, F., Schupp, M., Lazar, M.A., Reiner, S.L. Activation of retinoic acid receptor-alpha favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol 2007, 37, 2396-2399
101. Locke, N.R., Patterson, S.J., Hamilton, M.J., Sly, L.M., Krystal, G., Levings, M.K. SHIP regulates the reciprocal development of T regulatory and Th17 cells. J Immunol 2009, 183, 975-983
102. Chen, H., Qin, J., Wei, P., Zhang, J., Li, Q., Fu, L., Li, S., Ma, C., Cong, B. Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells. Prostaglandins Leukot Essent Fatty Acids 2009, 80, 195-200
103. Mirshafiey, A., Jadidi-Niaragh, F. Immunopharmacological role of the leukotriene receptor antagonists and inhibitors of leukotrienes generating enzymes in multiple sclerosis. Immunopharmacol Immunotoxicol 2010, 32, 219-227
104. Mirshafiey, A., Jadidi-Niaragh, F. Prostaglandins in pathogenesis and treatment of multiple sclerosis. Immunopharmacol Immunotoxicol 2010, 32, 543-554
105. Li, Q., Wang, Y., Chen, K., Zhou, Q., Wei, W., Wang, Y., Wang, Y. The role of oxidized low-density lipoprotein in breaking peripheral Th17/Treg balance in patients with acute coronary syndrome. Biochem Biophys Res Commun 2010, 394, 836-842
106. Reynolds, A.D., Stone, D.K., Hutter, J.A., Benner, E.J., Mosley, R.L., Gendelman, H.E. Regulatory T cells attenuate Th17 cellmediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol 2010, 184, 2261-2271
107. Fletcher, J.M., Lonergan, R., Costelloe, L., Kinsella, K., Moran, B., O'Farrelly, C., Tubridy, N., Mills, K.H. CD39+Foxp3+ regulatory T Cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 2009, 183, 7602-7610
108. Du, J., Huang, C., Zhou, B., Ziegler, S.F. Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol 2008, 180, 4785-4792
109. Ayyoub, M., Deknuydt, F., Raimbaud, I., Dousset, C., Leveque, L., Bioley, G., Valmori, D. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the T(H)17 lineagespecific transcription factor RORgamma t. Proc Natl Acad Sci USA 2009, 106, 8635-8640
110. Ichiyama, K., Yoshida, H., Wakabayashi, Y., Chinen, T., Saeki, K., Nakaya, M., Takaesu, G., Hori, S., Yoshimura, A., Kobayashi, T. Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J Biol Chem 2008, 283, 17003-17008
111. Osorio, F., LeibundGut-Landmann, S., Lochner, M., Lahl, K., Sparwasser, T., Eberl, G., Reis e Sousa, C. DC activated via dectin-1 convert Treg into IL-17 producers. Eur J Immunol 2008, 38, 3274-3281
112. Koenen, H.J., Smeets, R.L., Vink, P.M., van Rijssen, E., Boots, A.M., Joosten, I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008, 112, 2340-2352
113. Floess, S., Freyer, J., Siewert, C., Baron, U., Olek, S., Polansky, J., Schlawe, K., Chang, H.D., Bopp, T., Schmitt, E., Klein-Hessling, S., Serfling, E., Hamann, A., Huehn, J. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007, 5, e38
114. Janson, P.C., Winerdal, M.E., Marits, P., Thörn, M., Ohlsson, R., Winqvist, O. FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS ONE 2008, 3, e1612
115. Afzali, B., Mitchell, P., Lechler, R.I., John, S., Lombardi, G. Translational mini-review series on Th17 cells: Induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 2010, 59, 120-130
116. Zheng, S.G., Wang, J., Horwitz, D.A. Cutting edge: Foxp3+CD4+CD25+ regulatory T cells induced by IL-2 and TGFbeta are resistant to Th17 conversion by IL-6. J Immunol 2008, 180, 7112-7116
117. Chung, Y., Chang, S.H., Martinez, G.J., Yang, X.O., Nurieva, R., Kang, H.S., Ma, L., Watowich, S.S., Jetten, A.M., Tian, Q., Dong, C. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 2009, 30, 576-587
118. Pène, J., Chevalier, S., Preisser, L., Vénéreau, E., Guilleux, M.H., Ghannam, S., Molès, J.P., Danger, Y., Ravon, E., Lesaux, S., Yssel, H., Gascan, H. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol 2008, 180, 7423-7430
119. Beriou, G., Costantino, C.M., Ashley, C.W., Yang, L., Kuchroo, V.K., Baecher-Allan, C., Hafler, D.A. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 2009, 113, 4240-4249
120. Wright, G.P., Ehrenstein, M.R., Stauss, H.J. Regulatory T-cell adoptive immunotherapy: Potential for treatment of autoimmunity. Expert Rev Clin Immunol 2011, 7, 213-225
121. Hansen, W., Westendorf, A.M., Buer, J. Regulatory T cells as targets for immunotherapy of autoimmunity and inflammation. Inflamm Allergy Drug Targets 2008, 7, 217-223
122. Haak, S., Gyülveszi, G., Becher, B. Th17 cells in autoimmune disease: Changing the verdict. Immunotherapy 2009, 1, 199-203