Molecular Mechanisms of the Action of Vitamin A in Th17/Treg Axis in Multiple Sclerosis

Journal of Molecular Neuroscience

Volumn 57, Issue 4, 2015, Pages 605-613

  Abdolahi, Mina ^a   Yavari, Parvaneh ^a   Honarvar, Niyaz Mohammadzadeh ^a   Bitarafan, Sama ^b   Mahmoudi, Maryam ^a   Saboor Yaraghi, Ali Akbar ^a,c  

^a TEHRAN UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^b TEHRAN UNIVERSITY OF MEDICAL SCIENCES   (Iran)

^c TEHRAN UNIVERSITY OF MEDICAL SCIENCES   (Iran)

Author keywords

Multiple sclerosis; Regulatory T cell; T helper 17 cell; Vitamin A

Indexed keywords

CELL NUCLEUS RECEPTOR; GAMMA INTERFERON; GRANULOCYTE MACROPHAGE COLONY STIMULATING FACTOR; INTERLEUKIN 10; INTERLEUKIN 17; INTERLEUKIN 17F; INTERLEUKIN 1BETA; INTERLEUKIN 2; INTERLEUKIN 21; INTERLEUKIN 22; INTERLEUKIN 23; INTERLEUKIN 35; INTERLEUKIN 6; INTERLEUKIN 9; RETINOL; STAT3 PROTEIN; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; VITAMIN;

DRUG MECHANISM; HUMAN; IMMUNOPATHOGENESIS; MULTIPLE SCLEROSIS; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW; TH17 CELL; ANIMAL; DRUG EFFECTS; IMMUNOLOGY;

ANIMALS; HUMANS; MULTIPLE SCLEROSIS; T-LYMPHOCYTES, REGULATORY; TH17 CELLS; VITAMIN A; VITAMINS;

EID: 84947024737     PISSN: 08958696     EISSN: 15591166     Source Type: Journal    
DOI: 10.1007/s12031-015-0643-1     Document Type: Review

References (117)

1. Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ (2007) All-trans retinoic acid mediates enhanced Treg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 204(8):1765–1774
2. Bettelli E, Korn T, Kuchroo VK (2007) Th17: the third member of the effector T cell trilogy. Curr Opin Immunol 19:652–657
3. Beyeen AD, Adzemovic MZ, Ockinger J et al (2010) IL-22RA2 associates with multiple sclerosis and macrophage effector mechanisms in experimental neuroinflammation. J Immunol 185(11):6883–6890
4. Boks MA, Kager-Groenland JR, Haasjes MS, Zwaginga JJ, van Ham SM, ten Brinke A (2012) IL-10-generated tolerogenic dendritic cells are optimal for functional regulatory T cell induction—a comparative study of human clinical-applicable DC. Clin Immunol 142(3):332–342
5. Boppana S, Huang H, Ito K, Dhib-Jalbut S (2011) Immunologic aspects of multiple sclerosis. Mt Sinai J Med 78(2):207–220
6. Buc M (2013) Role of regulatory T cells in pathogenesis and biological therapy of multiple sclerosis. Mediat Inflamm 2013:963748
7. Cassani B, Villablanca EJ, De Calisto J, Wang S, Mora JR (2012) Vitamin A and immune regulation: role of retinoic acid in gut-associated dendritic cell education, immune protection and tolerance. Mol Asp Med 33(1):63–76
8. Chabaud M, Fossiez F, Taupin JL, Miossec P (1998) Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol 161:409–414
9. Chang J, Thangamani S, Kim MH, Ulrich B, Morris SM, Kim CH (2013) Retinoic acid promotes the development of Arg1-expressing dendritic cells for the regulation of T-cell differentiation. Eur J Immunol 43(4):967–978
10. Chen W, Jin W, Hardegen N et al (2003) Conversion of peripheral CD4 + CD25− naive T cells to CD4 + CD25+ regulatory T cells by TGF-β induction of transcription factor FoxP3. J Exp Med 198(12):1875–1886
11. Chen Z, Laurence A, Kanno Y et al (2006) Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci U S A 103:8137–8142
12. Collison LW, Workman CJ, Kuo TT et al (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450(7169):566–569
13. Comabella M, Khoury SJ (2012) Immunopathogenesis of multiple sclerosis. Clin Immunol 142(1):2–8
14. Coombes JL, Siddiqui KR, Arancibia-Cárcamo CV et al (2007) A functionally specialized population of mucosal CD103+ DCs induces FoxP3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J Exp Med 204(8):1757–1764
15. Coquet JM, Middendorp S, van der Horst G et al (2013) The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity. Immunity 38:53–65
16. Correale J, Villa A (2010) Role of CD8+ CD25+ Foxp3+ regulatory T cells in multiple sclerosis. Ann Neurol 67:625–638
17. Croxford JL, Feldmann M, Chernajovsky Y, Baker D (2001) Different therapeutic outcomes in experimental allergic encephalomyelitis dependent upon the mode of delivery of IL-10: a comparison of the effects of protein, adenoviral or retroviral IL-10 delivery into the central nervous system. J Immunol 166(6):4124–4130
18. Cua DJ, Hutchins B, LaFace DM, Stohlman SA, Coffman RL (2001) Central nervous system expression of IL-10 inhibits autoimmune encephalomyelitis. J Immunol 166(1):602–608
19. Den Hartog G, van Altena C, Savel koul HF, van Neerven RJ (2013) The mucosal factors retinoic acid and TGF-beta1 induce phenotypically and functionally distinct dendritic cell types. Int Arch Allergy Immunol 162(3):225–236
20. Dong S, Tweardy DJ (2002) Interactions of STAT5b-RARα, a novel acute promyelocytic leukemia fusion protein, with retinoic acid receptor and STAT3 signaling pathways. Blood 99(8):2637–2646
21. Durelli L, Conti L, Clerico M et al (2009) T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta. Ann Neurol 65(5):499–509
22. Duriancik DM, Lackey DE, Hoag KA (2010) Vitamin A as a regulator of antigen presenting cells. J Nutr 140:1395–1399
23. El-Behi M, Rostami A, Ciric B (2010) Current views on the roles of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. J Neuroimmune Pharmacol 5:189–197
24. Elias KM, Laurence A, Davidson TS et al (2008) Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111(3):1013–1020
25. Elyaman W, Bradshaw EM, Uyttenhove C et al (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci U S A 106:12885–12890
26. Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8:1254–1266
27. Ertesvag A, Engedal N, Naderi S, Blomhoff HK (2002) Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement of retinoic acid receptor-mediated IL-2 secretion. J Immunol 169(10):5555–5563
28. Ferrari CC, Depino AM, Prada F et al (2004) Reversible demyelination, blood–brain barrier breakdown, and pronounced neutrophil recruitment induced by chronic IL-1 expression in the brain. Am J Pathol 165:1827–1837
29. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY (2005) A function for interleukin 2 in FoxP3-expressing regulatory T cells. Nat Immunol 6(11):1142–1151
30. Gärtner D, Hoff H, Gimsa U, Burmester GR, Brunner-Weinzierl MC (2006) CD25 regulatory T cells determine secondary but not primary remission in EAE: impact on long-term disease progression. J Neuroimmunol 172(12):73–84
31. Hall JA, Grainger JR, Spencer SP, Belkaid Y (2011) The role of retinoic acid in tolerance and immunity. Immunity 35(1):13–22
32. Hamza T, Barnett JB, Li B (2010) Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci 11(3):789–806
33. Han L, Yang J, Wang X, Li D, Lv L, Li B (2015) Th17 cells in autoimmune diseases. Front Med 9:10–19
34. Hedegaard CJ, Krakauer M, Bendtzen K, Lund H, Sellebjerg F, Nielsen CH (2008) T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis. Immunology 125(2):161–169
35. Hofstetter H, Gold R, Hartung HP (2009) Th17 cells in MS and experimental autoimmune encephalomyelitis. Int MS J 16:12–18
36. Huan J, Culbertson N, Spencer L et al (2005) Decreased FOXP3 levels in multiple sclerosis patients. J Neurosci Res 81:45–52
37. Ito S, Ansari P, Sakatsume M et al (1999) Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma-induced genes by suppressing tyrosine phosphorylation of STAT1. Blood 93(5):1456–1463
38. Ivanov II, McKenzie BS, Zhou L et al (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133
39. Ivanov II, Zhou L, Littman DR (2007) Transcriptional regulation of Th17 cell differentiation. Semin Immunol
40. Jadidi-Niaragh F, Mirshafiey A (2011) Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J Immunol 74(1):1–13
41. Jafarirad S, Siassi F, Harirchian MH et al (2012) The effect of vitamin A supplementation on stimulated T-cell proliferation with myelin oligodendrocyte glycoprotein in patients with multiple sclerosis. J Neurosci Rural Pract 3(3):294–298
42. Jamshidian A, Shaygannejad V, Pourazar A, Zarkesh-Esfahani SH, Gharagozloo M (2013) Biased Treg/Th17 balance away from regulatory toward inflammatory phenotype in relapsed multiple scleroses and its correlation with severity of symptoms. J Neuroimmunol 262:106–112
43. Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564
44. Jovanovic DV, Di Battista JA, Martel-Pelletier J et al (1998) IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160:3513–3521
45. Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH (2007) Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol 179(6):3724–3733
46. Kim CH (2008) Regulation of FoxP3 regulatory T cells and Th17 cells by retinoids. Clin Dev Immunol 2008:416910
47. Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40:1830–1835
48. Klemann C, Raveney BJ, Klemann AK et al (2009) Synthetic retinoid AM80 inhibits Th17 cells and ameliorates experimental autoimmune encephalomyelitis. Am J Pathol 174(6):2234–2245
49. Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK (2005) Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med 202(10):1375–1386
50. Kohm AP, Carpentier PA, Anger HA, Miller SD (2002) Cutting edge: CD4+ CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis. J Immunol 169(9):4712–4716
51. Komiyama Y, Nakae S, Matsuki T et al (2006) IL-17 plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol 177:566–573
52. Kryczek I, Wei S, Vatan L et al (2007a) Cutting edge: opposite effects of IL-1 and IL-2 on the regulation of IL-17+ T cell pool IL-1 subverts IL-2-mediated suppression. J Immunol 179:1423–1426
53. Kryczek I, Wei S, Zou L et al (2007b) Cutting edge: Th17 and regulatory T cell dynamics and the regulation by IL-2 in the tumor microenvironment. J Immunol 178:6730–6733
54. Langrish CL, Chen Y, Blumenschein WM et al (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201(2):233–240
55. Laurence A, Tato CM, Davidson TS et al (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381
56. Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99
57. Lin JX, Leonard WJ (2000) The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19(21):2566–2576
58. Lin JT, Martin SL, Xia L, Gorham JD (2005) TGFbeta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol 174(10):5950–5958
59. Lock C, Hermans G, Pedotti R et al (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8(5):500–508
60. Lovett-Racke AE, Yang Y, Racke MK (2011) Th1 versus Th17: are T cell cytokines relevant in multiple sclerosis? Biochim Biophys Acta 1812(2):246–251
61. Lu L, Zhou X, Wang J, Zheng SG, Horwitz DA (2010) Characterization of protective human CD4CD25 FOXP3 regulatory T cells generated with IL-2, TGF-β and retinoic acid. PLoS One 5(12), e15150
62. Maddur MS, Miossec P, Kaveri SV, Bayry J (2012) Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am J Pathol 181(1):8–18
63. Massacesi L, Abbamondi AL, Giorgi C, Sarlo F, Lolli F, Amaducci L (1987) Suppression of experimental allergic encephalomyelitis by retinoic acid. J Neurol Sci 80:55–64
64. Matsuda M, Salazar F, Petersson M et al (1994) Interleukin 10 pretreatment protects target cells from tumor and allo-specific cytotoxic T cells and downregulates HLA class I expression. J Exp Med 180(6):2371–2376
65. Matusevicius D, Kivisakk P, He B et al (1999) Interleukin-17 mRNA expression in blood and CSF mononuclear cells is augmented in multiple sclerosis. Mult Scler 5:101–104
66. McGeachy MJ, Bak-Jensen KS, Chen Y et al (2007) TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat Immunol 8(12):1390–1397
67. McGeachy MJ, Chen Y, Tato CM et al (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10:314–324
68. Mohammadzadeh Honarvar N, Harirchian MH, Koohdani F et al (2013) The effect of vitamin A supplementation on retinoic acid-related orphan receptor γt (RORγt) and interleukin-17 (IL-17) gene expression in Avonex-treated multiple sclerotic patients. J Mol Neurosci 51(3):749–753
69. Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765
70. Mucida D, Park Y, Kim G (2007) Reciprocal Th17 and regulatory T cell differentiation mediated by retinoic acid. Science 317(5835):256–260
71. Mucida D, Park Y, Cheroutre H (2009a) From the diet to the nucleus: vitamin A and TGF-b join efforts at the mucosal interface of the intestine. Semin Immunol 21:14–21
72. Mucida D, Pino-Lagos K, Kim G et al (2009b) Retinoic acid can directly promote TGF-beta-mediated Foxp3 (+) Treg cell conversion of naive T cells. Immunity 30(4):471–472
73. Niedbala W, Wei XQ, Cai B et al (2007) IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. Eur J Immunol 37(11):3021–3029
74. Nowak EC, Weaver CT, Turner H et al (2009) IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med 206:1653–1660
75. Nurieva R, Yang XO, Martinez G et al (2007) Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448(7152):480–483
76. Okuda Y, Sakoda S, Bernard CC et al (1998) IL-6-deficient mice are resistant to the induction of experimental autoimmune encephalomyelitis provoked by myelin oligodendrocyte glycoprotein. Int Immunol 10:703–708
77. H17 cells. Nat Rev Neurol 7:303
78. Penkowa M, Hidalgo J (2001) Metallothionein treatment reduces proinflammatory cytokines IL-6 and TNF-alpha and apoptotic cell death during experimental autoimmune encephalomyelitis (EAE). Exp Neurol 170:1–14
79. Pino-Lagos K, Benson MJ, Noelle RJ (2008) Retinoic acid in the immune system. Ann N Y Acad Sci 1143:170–187
80. Pittock SJ, Lucchinetti CF (2007) The pathology of MS: new insights and potential clinical applications. Neurologist 13:45–56
81. Racke MK, Burnett D, Pak SH et al (1995) Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol 154:450–458
82. Rodgers JM, Miller SD (2012) Cytokine control of inflammation and repair in the pathology of multiple sclerosis. Yale J Biol Med 85(4):447–468
83. Ross AC (2012) Vitamin A and retinoic acid in T cell-related immunity. Am J Clin Nutr 96(5):1166–1172
84. Runia TF, Hop WCJ, Rijke B, Hintzen RQ (2014) Vitamin A is not associated with exacerbations in multiple sclerosis. Mult Scler Relat Disord 3:34–39
85. Sakaguchi S, Miyara M, Costantino CM, Hafler DA (2010) FOXP3+ regulatory T cells in the human immune system. Nat Rev Immunol 10:490–500
86. Samarut E, Rochette-Egly C (2011) Nuclear retinoic acid receptors: conductors of the retinoic acid symphony during development. Mol Cell Endocrinol 348(2):348–360
87. Samoilova EB, Horton JL, Hilliard B, Liu TS, Chen Y (1998) IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 161:6480–6486
88. Schambach F, Schupp M, Lazar MA, Reiner SL (2007) Activation of retinoic acid receptor-α favours regulatory T cell induction at the expense of IL-17-secreting T helper cell differentiation. Eur J Immunol 37(9):2396–2399
89. Setoguchi R, Hori S, Takahashi T, Sakaguchi S (2005) Homeostatic maintenance of natural FoxP3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201(5):723–735
90. Sommer A, Vyas KS (2012) A global clinical view on vitamin A and carotenoids. Am J Clin Nutr 96:1204S–1206S
91. Sonobe Y, Jin S, Wang J et al (2007) Chronological changes of CD4(+) and CD8(+) T cell subsets in the experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Tohoku J Exp Med 213:329–339
92. Steinman L (2014) Immunology of relapse and remission in multiple sclerosis. Annu Rev Immunol 32:257–281
93. Sun CM, Hall JA, Blank RB et al (2007) Small intestine lamina propria dendritic cells promote de novo generation of FoxP3 Treg cells via retinoic acid. J Exp Med 204(8):1775–1785
94. Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC (2006) A crucial role for interleukin (IL)- 1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203(7):1685–1691
95. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH (2009) Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31(2):331–341
96. Takahashi H, Kanno T, Nakayamada S et al (2012) TGF-b and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat Immunol 13:587–595
97. Ten Dijke P, Hill CS (2004) New insights into TGFbeta-Smad signalling. Trends Biochem Sci 29(5):265–273
98. Tzartos JS, Friese MA, Craner MJ et al (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172:146–155
99. Vaknin-Dembinsky A, Balashov K, Weiner HL (2006) IL-23 is increased in dendritic cells in multiple sclerosis and down-regulation of IL-23 by antisense oligos increases dendritic cell IL-10 production. J Immunol 176:7768–7774
100. Veldhoen M, Stockinger B (2006) TGFbeta1, a jack of all trades: the link with pro-inflammatory IL-17-producing T cells. Trends Immunol 27(8):358–361
101. Venken K, Hellings N, Hensen K et al (2006) Secondary progressive in contrast to relapsing-remitting multiple sclerosis patients show a normal CD4+ CD25+ regulatory T-cell function and FOXP3 expression. J Neurosci Res 83(8):1432–1446
102. Vojdani A, Lambert J (2011) The role of Th17 in neuroimmune disorders: target for CAM therapy. Evid Based Complement Alternat Med 2011:927294
103. von Boehmer H (2007) Oral tolerance: is it all retinoic acid? J Exp Med 204:1737
104. Wang X, Allen C, Ballow M (2007) Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-α from LPS-stimulated monocytes/macrophages. J Clin Immunol 27(2):193–200
105. Weaver CT, Hatton RD (2009) Interplay between the Th17 and Treg cell lineages: a (co)evolutionary perspective. Nat Rev Immunol 9:883–889
106. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688
107. Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN (2012) IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol 129(1):207–215
108. Wilson NJ, Boniface K, Chan JR et al (2007) Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 8:950–957
109. Wolf G (2006) Is 9-cis-retinoic acid the endogenous ligand for the retinoic acid-X receptor? Nutr Rev 64:532–538
110. Wrana JL (2002) Phosphoserine-dependent regulation of protein-protein interactions in the Smad pathway. Structure 10(1):5–7
111. Xiao S, Jin H, Korn T et al (2008) Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 181(4):2277–2284
112. Yang XO, Panopoulos AD, Nurieva R et al (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363
113. Yao Z, Kanno Y, Kerenyi M et al (2007) Nonredundant roles for Stat5a/b in directly regulating FoxP3. Blood 109(10):4368–4375
114. Yurchenko E, Shio MT, Huang TC et al (2012) Inflammation driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 effectors is abrogated by mTOR inhibition in vivo. PLoS One 7(4), e35572
115. Zhang X, Reddy J, Ochi H, Frenkel D, Kuchroo VK, Weiner HL (2006) Recovery from experimental allergic encephalomyelitis is TGF-beta dependent and associated with increases in CD4+ LAP+ and CD4+ CD25+ T cells. Int Immunol 18(4):495–503
116. Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA (2004) Natural and induced CD4+ CD25+ cells educate CD4+ CD25− cells to develop suppressive activity: the role of IL-2, TGF-β, and IL-10. J Immunol 172(9):5213–5221
117. Ziegler SF, Buckner JH (2009) FOXP3 and the regulation of Treg/Th17 differentiation. Microbes Infect 11:594–598