The role of FOXP3 in regulating immune responses

International Reviews of Immunology

Volumn 33, Issue 2, 2014, Pages 110-128

  Vent Schmidt, Jens ^a   Han, Jonathan M ^a   Macdonald, Katherine G ^a   Levings, Megan K ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

FOXP3; Plasticity; T regulatory cells; Th17 cells; Tolerance

Indexed keywords

GAMMA INTERFERON; INTERLEUKIN 2; INTERLEUKIN 4; RETINOID RELATED ORPHAN RECEPTOR GAMMA; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR T BET;

ARTICLE; CELL FUNCTION; CHROMATIN ASSEMBLY AND DISASSEMBLY; ENZYME REPRESSION; EPIGENETICS; GENE EXPRESSION; HELPER CELL; HUMAN; IMMUNE RESPONSE; INTRACELLULAR SIGNALING; LANDSCAPE; MEMBRANE STABILIZATION; NONHUMAN; PHENOTYPE; POSITIVE FEEDBACK; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN STRUCTURE; REGULATORY T LYMPHOCYTE; STABLE EXPRESSION; T FOLLICULAR HELPER CELL; T LYMPHOCYTE; TH1 CELL; TH2 CELL;

ANIMALS; CELL DIFFERENTIATION; CELL LINEAGE; FEEDBACK, PHYSIOLOGICAL; FORKHEAD TRANSCRIPTION FACTORS; GENE REGULATORY NETWORKS; HOMEOSTASIS; HUMANS; IMMUNE TOLERANCE; SIGNAL TRANSDUCTION; T-LYMPHOCYTE SUBSETS; T-LYMPHOCYTES, REGULATORY;

EID: 84896109168     PISSN: 08830185     EISSN: 15635244     Source Type: Journal    
DOI: 10.3109/08830185.2013.811657     Document Type: Article

References (152)

1. Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol 2003;21:139-176. (Pubitemid 37174529)
2. von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol 1990;8:531-556. (Pubitemid 20135638)
3. Miller JF,Morahan G. Peripheral T cell tolerance. Annu Rev Immunol 1992;10:51-69.
4. Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133(5):775-787. (Pubitemid 351707693)
5. McMurchy AN, Bushell A, Levings MK,Wood KJ.Moving to tolerance: clinical application of T regulatory cells. Semin Immunol 2011;23(4):304-313.
6. Sakaguchi S, Sakaguchi N, Asano M, et al. 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(3):1151-1164.
7. Levings MK, Sangregorio R, RoncaroloMG.Human cd25(+)cd4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 2001;193(11):1295-1302.
8. Shevach EM. Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 2001;193(11):F41-F46.
9. Hori S,Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299(5609):1057-1061. (Pubitemid 36222930)
10. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003;4(4):337-342. (Pubitemid 36432315)
11. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25 +regulatory T cells. Nat Immunol 2003;4(4):330-336. (Pubitemid 36432314)
12. Brunkow ME, Jeffery EW, Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 2001;27(1):68-73. (Pubitemid 32044521)
13. Bennett CL,Christie J,Ramsdell F, et al.Theimmune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused bymutations of FOXP3. Nat Genet 2001;27(1):20-21.
14. Schubert LA, Jeffery E, Zhang Y, et al. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 2001;276(40):37672-37679.
15. Bacchetta R, Passerini L, Gambineri E, et al. Defective regulatory and effector T cell functions in patients with FOXP3mutations. J Clin Invest. 2006;116(6):1713-1722.
16. Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol 2012;3:211.
17. Allan SE, Crome SQ, CrellinNK, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007;19(4):345-354. (Pubitemid 46523383)
18. Ziegler SF. FOXP3: not just for regulatory T cells anymore. Eur J Immunol 2007;37(1):21-23. (Pubitemid 46128782)
19. McMurchy AN, Di Nunzio S, Roncarolo MG, et al.. Molecular regulation of cellular immunity by FOXP3. Adv ExpMed Biol 2009;665:30-46.
20. Gavin MA, Torgerson TR, Houston E, et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc Natl Acad Sci USA 2006;103(17):6659-6664.
21. Morgan ME, van Bilsen JH, Bakker AM, et al. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum Immunol 2005;66(1):13-20. (Pubitemid 40037706)
22. Tran DQ, Ramsey H, Shevach EM. 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 2007;110(8):2983-2990. (Pubitemid 350006952)
23. Broady R, Yu J, Levings MK. ATG-induced expression of FOXP3 in human CD4(+) T cells in vitro is associated with T-cell activation and not the induction of FOXP3(+) T regulatory cells. Blood 2009;114(24):5003-5006.
24. Pillai V, Ortega SB, Wang CK, Karandikar NJ. Transient regulatory T-cells: a state attained by all activated human T-cells. Clin Immunol 2007;123(1):18-29. (Pubitemid 46401504)
25. Zheng Y, Manzotti CN, Burke F, et al. Acquisition of suppressive function by activated human CD4 +CD25- T cells is associated with the expression of CTLA-4 not FoxP3. J Immunol 2008;181(3):1683-1691.
26. Allan SE, Alstad AN,Merindol N, et al. Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3.MolTher 2008;16(1):194-202.
27. Allan SE, Song-Zhao GX, Abraham T, et al.. Inducible reprogramming of human T cells into Treg cells by a conditionally active formof FOXP3. Eur J Immunol 2008;38(12):3282-3289.
28. Fu W, Ergun A, Lu T, et al. Amultiply redundant genetic switch locks in the transcriptional signature of regulatory T cells. Nat Immunol 2012;13(10):972-980.
29. Hori S. The Foxp3 interactome: a network perspective of T(reg) cells. Nat Immunol 2012;13(10):943-945.
30. Rudra D, deRoos P, Chaudhry A, et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 2012;13(10):1010-1019.
31. Ziegler SF. FOXP3: of mice andmen. Annu Rev Immunol 2006;24:209-226.
32. Lopes JE, Torgerson TR, Schubert LA, et al. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J Immunol 2006;177(5):3133-3142. (Pubitemid 44277831)
33. Zheng Y, Josefowicz SZ, Kas A, et al.. Genome-wide analysis of Foxp3 target genes in developing andmature regulatory T cells. Nature 2007;445(7130):936-940.
34. Marson A, Kretschmer K, Frampton GM, et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 2007;445(7130):931-935.
35. Wu Y, BordeM,Heissmeyer V, et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006;126(2):375-387. (Pubitemid 44092960)
36. Buckner JH, Ziegler SF. Functional analysis of FOXP3. Ann NY Acad Sci 2008;1143:151-169.
37. Li B, SamantaA, SongX, et al.FOXP3 ensembles in T-cell regulation. Immunol Rev 2006;212:99-113. (Pubitemid 44116703)
38. Chae WJ, Henegariu O, Lee SK, Bothwell AL. The mutant leucine-zipper domain impairs both dimerization and suppressive function of Foxp3 in T cells. Proc Natl Acad Sci USA 2006;103(25):9631-9636. (Pubitemid 43955876)
39. Li B, Samanta A, Song X, et al. FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX autoimmune disease. Int Immunol 2007;19(7):825-835. (Pubitemid 47241891)
40. Li B, GreeneMI. FOXP3 actively represses transcription by recruiting the HAT/HDAC complex. Cell Cycle 2007;6(12):1432-1436.
41. Li B, Samanta A, Song X, et al. FOXP3 interactionswith histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci USA 2007;104(11):4571-4576. (Pubitemid 47186266)
42. Allan SE, Passerini L, Bacchetta R, et al.The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 2005;115(11):3276-3284. (Pubitemid 41567592)
43. Du J, Huang C, Zhou B, Ziegler SF. Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol 2008;180(7):4785-4792.
44. Smith EL, Finney HM, Nesbitt AM, et al. Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation. Immunology 2006;119(2):203-211. (Pubitemid 44401639)
45. Krejsgaard T, Gjerdrum LM, Ralfkiaer E, et al.Malignant Tregs express low molecular splice forms of FOXP3 in Sezary syndrome. Leukemia 2008;22(12):2230-2239.
46. Bettelli E, Dastrange M, Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NFkappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci USA 2005;102(14):5138-5143.
47. Ono M, Yaguchi H, Ohkura N, et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007;446(7136):685-689. (Pubitemid 46606883)
48. Marwaha AK, Leung NJ,McMurchy AN, Levings MK. TH17 Cells in Autoimmunity and Immunodeficiency: Protective or Pathogenic? Front Immunol 2012;3:129.
49. Zhou L, Lopes JE, Chong MM, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008;453(7192):236-240. (Pubitemid 351667978)
50. Yang XO, Nurieva R, Martinez GJ, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008;29(1):44-56.
51. TaoR,deZoetenEF, Ozkaynak E, et al.Deacetylase inhibitionpromotes the generation and function of regulatory T cells. NatMed 2007;13(11):1299-1307. (Pubitemid 350073591)
52. Finnin MS, Donigian JR, Cohen A, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999;401(6749):188-193. (Pubitemid 29436325)
53. Wang L, Tao R,Hancock WW. Using histone deacetylase inhibitors to enhance Foxp3(+) regulatory T-cell function and induce allograft tolerance. Immunol Cell Biol 2009;87(3):195-202.
54. Chen C, Rowell EA, Thomas RM, et al. Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J Biol Chem 2006;281(48):36828-36834. (Pubitemid 46042151)
55. Camperio C, Caristi S, Fanelli G, et al. Forkhead transcription factor FOXP3 upregulates CD25 expression through cooperation with RelA/NF-kappaB. PLoS One 2012;7(10):e48303.
56. Han JM, Patterson SJ, LevingsMK. The Role of the PI3K Signaling Pathway in CD4(+) T Cell Differentiation and Function. Front Immunol 2012;3:245.
57. Vaeth M, Schliesser U, Muller G, et al. Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3+ regulatory T cells. Proc Natl Acad Sci USA 2012;109(40):16258-16263.
58. Chen X, Oppenheim JJ.Thephenotypic and functional consequences of tumour necrosis factor receptor type 2 expression on CD4(+) FoxP3(+) regulatory T cells. Immunology 2011;133(4):426-433.
59. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010;236:219-242.
60. McHugh RS,WhittersMJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002;16(2):311-323. (Pubitemid 34211969)
61. Sakaguchi S. Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 2004;22:531-562. (Pubitemid 38680433)
62. De Rosa V, Procaccini C, Cali G, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 2007;26(2):241-255. (Pubitemid 46329441)
63. Schmetterer KG, Neunkirchner A, PicklWF. Naturally occurring regulatory T cells:markers,mechanisms, andmanipulation. FASEB J 2012;26(6):2253-2276.
64. LiuW, PutnamAL, Xu-Yu Z, et al. CD127 expression inversely correlateswith FoxP3 and suppressive function of human CD4+ T reg cells. J ExpMed 2006;203(7):1701-1711. (Pubitemid 44036276)
65. Seddiki N, Santner-Nanan B,Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J ExpMed 2006;203(7):1693-1700. (Pubitemid 44036275)
66. Zeiser R, Negrin RS. Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. Cell Cycle 2008;7(4):458-462. (Pubitemid 351366473)
67. Konig S, Probst-KepperM, Reinl T, et al. First insight into the kinome of human regulatory T cells. PLoS One 2012;7(7):e40896.
68. Boubali S, Liopeta K, Virgilio L, et al. Calcium/calmodulin-dependent protein kinase II regulates IL-10 production by human T lymphocytes: a distinct target in the calcium dependent pathway. Mol Immunol 2012;52(2):51-60.
69. CrellinNK,GarciaRV, LevingsMK.Altered activation ofAKTis required for the suppressive function of human CD4+CD25+ T regulatory cells. Blood 2007;109(5):2014-2022. (Pubitemid 46348201)
70. Patterson SJ,Han JM,Garcia R, et al. Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells. J Immunol 2011;186(10):5533-5537.
71. Bensinger SJ, Walsh PT, Zhang J, et al. Distinct IL-2 receptor signaling pattern in CD4+CD25 +regulatory T cells. J Immunol 2004;172(9):5287-5296. (Pubitemid 38542026)
72. Ouyang W, Liao W, Luo CT, et al. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 2012;491(7425):554-559.
73. Harada Y, Elly C, Ying G, et al. Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J ExpMed 2010;207(7):1381-1391.
74. Ouyang W, BeckettO,Ma Q, et al. Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol 2010;11(7):618-627.
75. Strauss L, CzystowskaM, Szajnik M, et al. Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS One 2009;4(6):e5994.
76. Battaglia M, Stabilini A, Migliavacca B, et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 2006;177(12):8338-8347. (Pubitemid 44893795)
77. Lu L, Qian XF, Rao JH, et al. Rapamycin promotes the expansion of CD4(+) Foxp3(+) regulatory T cells after liver transplantation. Transplant Proc. 2010;42(5):1755-1757.
78. Michalek RD, Gerriets VA, Jacobs SR, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011;186(6):3299-3303.
79. Laplante M, Sabatini DM.mTOR signaling at a glance. J Cell Sci 2009;122(Pt 20):3589-3594.
80. Isakov N, Altman A. PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors. Front Immunol 2012;3:273.
81. Zanin-Zhorov A, Ding Y, Kumari S, et al. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 2010;328(5976):372-376.
82. Vang KB, Yang J, Pagan AJ, et al. Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J Immunol 2010;184(8):4074- 4077.
83. Ruan Q, Kameswaran V, Tone Y, et al. Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 2009;31(6):932-940.
84. Loizou L, Andersen KG, Betz AG. Foxp3 interactswith c-Rel tomediateNF-kappaB repression. PLoS One 2011;6(4):e18670.
85. Oh-HoraM, Komatsu N, PishyarehM, et al. Agonist-Selected T Cell Development Requires Strong T Cell Receptor Signaling and Store-Operated Calcium Entry. Immunity 2013;38(5):881-895.
86. Cipolletta D, Feuerer M, Li A, et al. PPAR-gamma is amajor driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 2012;486(7404):549-553.
87. Choi JM, Bothwell AL. The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases.Mol Cells 2012;33(3):217-222.
88. Nie H, Zheng Y, Li R, et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. NatMed 2013;19(3):322-328.
89. Frauwirth KA, Riley JL,HarrisMH, et al.The CD28 signaling pathway regulates glucosemetabolism. Immunity 2002;16(6):769-777. (Pubitemid 34786476)
90. Jacobs SR,Herman CE,Maciver NJ, et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 2008;180(7):4476-4486.
91. Lu Y, Schneider H, Rudd CE. Murine regulatory T cells differ from conventional T cells in resisting the CTLA-4 reversal of TCR stop-signal. Blood 2012;120(23):4560-4570.
92. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms.Mol Cell Biol 2005;25(21):9543-9553. (Pubitemid 41507854)
93. Reissig S, Hovelmeyer N, Weigmann B, et al.The tumor suppressor CYLD controls the function of murine regulatory T cells. J Immunol 2012;189(10):4770-4776.
94. Chang JH, Xiao Y, Hu H, et al. Ubc13 maintains the suppressive function of regulatory T cells and prevents their conversion into effector-like T cells. Nat Immunol 2012;13(5):481-490.
95. Zorn E, Nelson EA, Mohseni M, et al. IL-2 regulates FOXP3 expression in human CD4+CD25 +regulatory T cells through a STAT-dependentmechanism and induces the expansion of these cells in vivo. Blood 2006;108(5):1571-1579. (Pubitemid 44316124)
96. Boyman O, Krieg C, Letourneau S, et al. Selectively expanding subsets of T cells in mice by injection of interleukin-2/antibody complexes: implications for transplantation tolerance. Transplant Proc 2012;44(4):1032-1034.
97. Garg G, Tyler JR, Yang JH, et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25 +regulatory T cell function. J Immunol 2012;188(9):4644-4653.
98. Tanaka K, Ichiyama K,HashimotoM, et al. Loss of suppressor of cytokine signaling 1 inhelper T cells leads to defective Th17 differentiation by enhancing antagonistic effects of IFN-gamma on STAT3 and Smads. J Immunol 2008;180(6):3746-3756.
99. Takahashi R, Nishimoto S, Muto G, et al. SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J Exp Med 2011;208(10):2055-2067.
100. 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(3):277-284. (Pubitemid 46745377)
101. Amendola M, Passerini L, Pucci F, et al. Regulated and multiple miRNA and siRNA delivery into primary cells by a lentiviral platform.MolTher 2009;17(6):1039-1052.
102. Zhou X, Bailey-Bucktrout SL, Jeker LT, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenicmemory T cells in vivo. Nat Immunol 2009;10(9):1000-1007.
103. Miyao T, Floess S, Setoguchi R, et al. Plasticity of foxp3(+) T cells reflects promiscuous foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012;36(2):262-275.
104. Kanhere A, Hertweck A, Bhatia U, et al. T-bet and GATA3 orchestrate Th1 andTh2 differentiation through lineage-specific targeting of distal regulatory elements. Nature Commun 2012;3:1268.
105. Crome SQ, Wang AY, Levings MK. Translational mini-review series on Th17 cells: function and regulation of human T helper 17 cells in health and disease. Clin Exp Immunol 2010;159(2):109-119.
106. Duhen T,Duhen R, Lanzavecchia A, et al. Functionally distinct subsets of humanFOXP3+Treg cells that phenotypically mirror effectorThcells. Blood 2012;119(19):4430-4440.
107. Wei J, Duramad O, Perng OA, et al. Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proc Natl Acad Sci USA 2007;104(46):18169-18174. (Pubitemid 350210839)
108. Sawitzki B, Kingsley CI, Oliveira V, et al. IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J ExpMed 2005;201(12):1925-1935. (Pubitemid 41002929)
109. Koenecke C, Lee CW, Thamm K, et al. IFN-gamma production by allogeneic Foxp3 +regulatory T cells is essential for preventing experimental graft-versus-host disease. J Immunol 2012;189(6):2890-2896.
110. Koch MA,Thomas KR, PerdueNR, et al. T-bet(+) Treg cells undergo abortiveTh1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 2012;37(3):501-510.
111. Hall AO, Beiting DP, Tato C, et al. The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 2012;37(3):511-523.
112. Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1-like, Foxp3 +regulatory T cells in human autoimmune disease. NatMed 2011;17(6):673-675.
113. McClymont SA, Putnam AL, Lee MR, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol 2011;186(7):3918-3926.
114. Mantel PY, Kuipers H, Boyman O, et al. GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol 2007;5(12):2847-2861. (Pubitemid 351159712)
115. KimBS, KimIK, Park YJ, et al. Conversion of Th2 memory cells into Foxp3+ regulatory T cells suppressing Th2-mediated allergic asthma. Proc Natl Acad Sci USA 2010;107(19):8742-8747.
116. Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007;445(7129):766-770. (Pubitemid 46279706)
117. Hansmann L, Schmidl C, Kett J, et al. Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression. J Immunol 2012;188(3):1275-1282.
118. ZhengY,ChaudhryA,Kas A, et al.RegulatoryT-cell suppressorprogramco-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009;458(7236):351-356.
119. Wang Y, Souabni A, Flavell RA,Wan YY. An intrinsic mechanism predisposes Foxp3-expressing regulatory T cells to Th2 conversion in vivo. J Immunol 2010;185(10):5983-5992.
120. Wang Y, Su MA, Wan YY. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 2011;35(3):337-348.
121. Wohlfert EA, Grainger JR, Bouladoux N, et al. GATA3 controls Foxp3(+) regulatory T cell fate during inflammation inmice. J Clin Invest 2011;121(11):4503-4515.
122. Krishnamoorthy N, Khare A, Oriss TB, et al. Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat Med 2012;18(10):1525-1530.
123. Zhang F, Meng G, Strober W. Interactions among the transcription factors Runx1, RORgammat and Foxp3 regulate the differentiation of interleukin 17-producing T cells. Nat Immunol 2008;9(11):1297-1306.
124. Ichiyama K, Yoshida H, Wakabayashi Y, et al. Foxp3 inhibits RORgammat-mediated IL- 17A mRNA transcription through direct interaction with RORgammat. J Biol Chem 2008; 283(25):17003-17008.
125. Jeron A, Hansen W, Ewert F, et al. ChIP-on-chip analysis identifies IL-22 as direct target gene of ectopically expressed FOXP3 transcription factor in human T cells. BMC Genomics 2012;13: 1-13.
126. Burgler S, Mantel PY, Bassin C, et al. RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter. J Immunol 2010;184(11):6161-6169.
127. Passerini L, Olek S, Di Nunzio S, 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(6):1376-1379.
128. Tartar DM, VanMorlan AM,Wan X, et al. FoxP3+RORgammat+T helper intermediates display suppressive function against autoimmune diabetes. J Immunol 2010;184(7):3377-3385.
129. Koenen HJ, Smeets RL, Vink PM, et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008;112(6):2340-2352.
130. Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30(6):899-911.
131. McMurchy AN, Gillies J, Gizzi MC, et al. A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells. Blood 2013;121(8):1265- 1275.
132. Chaudhry A, Rudra D, Treuting P, et al. CD4+ regulatory T cells control TH17 responses in a Stat3- dependentmanner. Science 2009;326(5955):986-991.
133. Yu D, Rao S, Tsai LM, et al.The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009;31(3):457-468.
134. Nurieva RI, Chung Y,Martinez GJ, et al. Bcl6mediates the development of T follicular helper cells. Science 2009;325(5943):1001-1005.
135. Linterman MA, Pierson W, Lee SK, et al. Foxp3+ follicular regulatory T cells control the germinal center response. NatMed 2011;17(8):975-982.
136. Chung Y, Tanaka S, Chu F, et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. NatMed 2011;17(8):983-988.
137. Wollenberg I, Agua-Doce A, Hernandez A, et al. Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J Immunol 2011;187(9):4553-4560.
138. Sawant DV, Sehra S, Nguyen ET, et al. Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing Gata3 function. J Immunol 2012;189(10):4759-4769.
139. Martins GA, Cimmino L, Shapiro-Shelef M, et al. Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat Immunol 2006;7(5):457-465.
140. Cretney E, Xin A, Shi W, et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 2011;12(4):304-311.
141. Thornton AM, Korty PE, Tran DQ, et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol 2010;184(7):3433-3441.
142. Richards EJ. Inherited epigenetic variation-revisiting soft inheritance. Nat Rev Genet 2006;7(5):395-401.
143. Schmidl C, KlugM, Boeld TJ, et al. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 2009;19(7):1165-1174.
144. Tian Y, Jia Z,Wang J, et al. Globalmapping of H3K4me1 and H3K4me3 reveals the chromatin statebased cell type-specific gene regulation in human Treg cells. PLoS One 2011;6(11):e27770.
145. Floess S, Freyer J, Siewert C, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007;5(2):e38.
146. Ohkura N, Hamaguchi M, Morikawa H, 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(5):785-799.
147. Samstein RM, Arvey A, Josefowicz SZ, et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012;151(1):153-166.
148. Holmes D,Gao J, Su L. Foxp3 inhibitsHDAC1 activity tomodulate gene expression in human T cells. Virology 2011;421(1):12-18.
149. Katoh H, Qin ZS, Liu R, et al. FOXP3 orchestrates H4K16 acetylation and H3K4 trimethylation for activation of multiple genes by recruiting MOF and causing displacement of PLU-1. Mol Cell 2011;44(5):770-784.
150. Pan F, Yu H, Dang EV, et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 2009;325(5944):1142-1146.
151. BettiniML, Pan F, Bettini M, et al. Loss of epigeneticmodification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity 2012;36(5):717-730.
152. Mackey-Cushman SL,Gao J,Holmes DA, et al. FoxP3 interactswith linker histone H1.5 to modulate gene expression and programTreg cell activity. Genes Immun 2011;12(7):559-567.