The Role of FOXP3 in Regulating Immune Responses

REFERENCES

• Starr TK, Jameson SC, Hogquist KA. Positive and negative selection of T cells. Annu Rev Immunol 2003;21:139–176.
   PubMed Web of Science ®Google Scholar
• von Boehmer H. Developmental biology of T cells in T cell-receptor transgenic mice. Annu Rev Immunol 1990;8:531–556.
   PubMedGoogle Scholar
• Miller JF, Morahan G. Peripheral T cell tolerance. Annu Rev Immunol 1992;10:51–69.
   PubMed Web of Science ®Google Scholar
• Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance. Cell 2008;133(5):775–787.
   PubMed Web of Science ®Google Scholar
• McMurchy AN, Bushell A, Levings MK, Wood KJ. Moving to tolerance: clinical application of T regulatory cells. Semin Immunol 2011;23(4):304–313.
   PubMed Web of Science ®Google Scholar
• Sakaguchi S, Sakaguchi N, Asano M, Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155(3):1151–1164.
   PubMed Web of Science ®Google Scholar
• Levings MK, Sangregorio R, Roncarolo MG. 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.
   PubMed Web of Science ®Google Scholar
• Shevach EM. Certified professionals: CD4(+)CD25(+) suppressor T cells. J Exp Med 2001;193(11):F41–F46.
   PubMed Web of Science ®Google Scholar
• Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299(5609):1057–1061.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Brunkow ME, Jeffery EW, Hjerrild KA, 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.
   PubMed Web of Science ®Google Scholar
• Bennett CL, Christie J, Ramsdell F, The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 2001;27(1):20–21.
   PubMed Web of Science ®Google Scholar
• Schubert LA, Jeffery E, Zhang Y, Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J Biol Chem 2001;276(40):37672–37679.
   PubMed Web of Science ®Google Scholar
• Bacchetta R, Passerini L, Gambineri E, Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest. 2006;116(6):1713–1722.
   PubMed Web of Science ®Google Scholar
• Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol 2012;3:211.
   PubMed Web of Science ®Google Scholar
• Allan SE, Crome SQ, Crellin NK, Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007;19(4):345–354.
   PubMed Web of Science ®Google Scholar
• Ziegler SF. FOXP3: not just for regulatory T cells anymore. Eur J Immunol 2007;37(1):21–23.
   PubMed Web of Science ®Google Scholar
• McMurchy AN, Di Nunzio S, Roncarolo MG, et al.. Molecular regulation of cellular immunity by FOXP3. Adv Exp Med Biol 2009;665:30–46.
   Google Scholar
• Gavin MA, Torgerson TR, Houston E, 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.
   PubMed Web of Science ®Google Scholar
• Morgan ME, van Bilsen JH, Bakker AM, Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum Immunol 2005;66(1):13–20.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Manzotti CN, Burke F, 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.
   Google Scholar
• Allan SE, Alstad AN, Merindol N, Generation of potent and stable human CD4+ T regulatory cells by activation-independent expression of FOXP3. Mol Ther 2008;16(1):194–202.
   Google Scholar
• Allan SE, Song-Zhao GX, Abraham T, et al.. Inducible reprogramming of human T cells into Treg cells by a conditionally active form of FOXP3. Eur J Immunol 2008;38(12):3282–3289.
   Google Scholar
• Fu W, Ergun A, Lu T, A multiply redundant genetic switch ‘locks in’ the transcriptional signature of regulatory T cells. Nat Immunol 2012;13(10):972–980.
   PubMed Web of Science ®Google Scholar
• Hori S. The Foxp3 interactome: a network perspective of T(reg) cells. Nat Immunol 2012;13(10):943–945.
   Google Scholar
• Rudra D, deRoos P, Chaudhry A, Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 2012;13(10):1010–1019.
   PubMed Web of Science ®Google Scholar
• Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol 2006;24:209–226.
   PubMed Web of Science ®Google Scholar
• Lopes JE, Torgerson TR, Schubert LA, Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J Immunol 2006;177(5):3133–3142.
   PubMed Web of Science ®Google Scholar
• Zheng Y, Josefowicz SZ, Kas A, et al.. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 2007;445(7130):936–940.
   PubMed Web of Science ®Google Scholar
• Marson A, Kretschmer K, Frampton GM, Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 2007;445(7130):931–935.
   Google Scholar
• Wu Y, Borde M, Heissmeyer V, FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006;126(2):375–387.
   PubMed Web of Science ®Google Scholar
• Buckner JH, Ziegler SF. Functional analysis of FOXP3. Ann NY Acad Sci 2008;1143:151–169.
   PubMed Web of Science ®Google Scholar
• Li B, Samanta A, Song X, FOXP3 ensembles in T-cell regulation. Immunol Rev 2006;212:99–113.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• Li B, Samanta A, Song X, 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.
   Google Scholar
• Li B, Greene MI. FOXP3 actively represses transcription by recruiting the HAT/HDAC complex. Cell Cycle 2007;6(12):1432–1436.
   Google Scholar
• Li B, Samanta A, Song X, FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci USA 2007;104(11):4571–4576.
   PubMed Web of Science ®Google Scholar
• Allan SE, Passerini L, Bacchetta R, The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J Clin Invest 2005;115(11):3276–3284.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• Smith EL, Finney HM, Nesbitt AM, Splice variants of human FOXP3 are functional inhibitors of human CD4+ T-cell activation. Immunology 2006;119(2):203–211.
   Google Scholar
• Krejsgaard T, Gjerdrum LM, Ralfkiaer E, Malignant Tregs express low molecular splice forms of FOXP3 in Sezary syndrome. Leukemia 2008;22(12):2230–2239.
   Google Scholar
• Bettelli E, Dastrange M, Oukka M. Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. Proc Natl Acad Sci USA 2005;102(14):5138–5143.
   PubMed Web of Science ®Google Scholar
• Ono M, Yaguchi H, Ohkura N, Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007;446(7136):685–689.
   PubMed Web of Science ®Google Scholar
• Marwaha AK, Leung NJ, McMurchy AN, Levings MK. TH17 Cells in Autoimmunity and Immunodeficiency: Protective or Pathogenic? Front Immunol 2012;3:129.
   PubMed Web of Science ®Google Scholar
• Zhou L, Lopes JE, Chong MM, TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008;453(7192):236–240.
   PubMed Web of Science ®Google Scholar
• Yang XO, Nurieva R, Martinez GJ, Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008;29(1):44–56.
   PubMed Web of Science ®Google Scholar
• Tao R, de Zoeten EF, Ozkaynak E, Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med 2007;13(11):1299–1307.
   PubMed Web of Science ®Google Scholar
• Finnin MS, Donigian JR, Cohen A, Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature 1999;401(6749):188–193.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• Chen C, Rowell EA, Thomas RM, Transcriptional regulation by Foxp3 is associated with direct promoter occupancy and modulation of histone acetylation. J Biol Chem 2006;281(48):36828–36834.
   Google Scholar
• Camperio C, Caristi S, Fanelli G, Forkhead transcription factor FOXP3 upregulates CD25 expression through cooperation with RelA/NF-kappaB. PLoS One 2012;7(10):e48303.
   Google Scholar
• Han JM, Patterson SJ, Levings MK. The Role of the PI3K Signaling Pathway in CD4(+) T Cell Differentiation and Function. Front Immunol 2012;3:245.
   PubMed Web of Science ®Google Scholar
• Vaeth M, Schliesser U, Muller G, 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.
   PubMed Web of Science ®Google Scholar
• Chen X, Oppenheim JJ. The phenotypic and functional consequences of tumour necrosis factor receptor type 2 expression on CD4(+) FoxP3(+) regulatory T cells. Immunology 2011;133(4):426–433.
   Google Scholar
• Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol Rev 2010;236:219–242.
   PubMed Web of Science ®Google Scholar
• McHugh RS, Whitters MJ, Piccirillo CA, CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity 2002;16(2):311–323.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• De Rosa V, Procaccini C, Cali G, A key role of leptin in the control of regulatory T cell proliferation. Immunity 2007;26(2):241–255.
   Google Scholar
• Schmetterer KG, Neunkirchner A, Pickl WF. Naturally occurring regulatory T cells: markers, mechanisms, and manipulation. FASEB J 2012;26(6):2253–2276.
   PubMed Web of Science ®Google Scholar
• Liu W, Putnam AL, Xu-Yu Z, CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 2006;203(7):1701–1711.
   PubMed Web of Science ®Google Scholar
• Seddiki N, Santner-Nanan B, Martinson J, Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006;203(7):1693–1700.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Konig S, Probst-Kepper M, Reinl T, First insight into the kinome of human regulatory T cells. PLoS One 2012;7(7):e40896.
   Google Scholar
• Boubali S, Liopeta K, Virgilio L, 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.
   Google Scholar
• Crellin NK, Garcia RV, Levings MK. Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells. Blood 2007;109(5):2014–2022.
   PubMed Web of Science ®Google Scholar
• Patterson SJ, Han JM, Garcia R, Cutting edge: PHLPP regulates the development, function, and molecular signaling pathways of regulatory T cells. J Immunol 2011;186(10):5533–5537.
   Google Scholar
• Bensinger SJ, Walsh PT, Zhang J, Distinct IL-2 receptor signaling pattern in CD4+CD25 +regulatory T cells. J Immunol 2004;172(9):5287–5296.
   PubMed Web of Science ®Google Scholar
• Ouyang W, Liao W, Luo CT, Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 2012;491(7425):554–559.
   PubMed Web of Science ®Google Scholar
• Harada Y, Elly C, Ying G, Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med 2010;207(7):1381–1391.
   PubMed Web of Science ®Google Scholar
• Ouyang W, Beckett O, Ma Q, Foxo proteins cooperatively control the differentiation of Foxp3+ regulatory T cells. Nat Immunol 2010;11(7):618–627.
   PubMed Web of Science ®Google Scholar
• Strauss L, Czystowska M, Szajnik M, Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS One 2009;4(6):e5994.
   Google Scholar
• Battaglia M, Stabilini A, Migliavacca B, 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.
   PubMed Web of Science ®Google Scholar
• Lu L, Qian XF, Rao JH, Rapamycin promotes the expansion of CD4(+) Foxp3(+) regulatory T cells after liver transplantation. Transplant Proc. 2010;42(5):1755–1757.
   Google Scholar
• Michalek RD, Gerriets VA, Jacobs SR, 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.
   PubMed Web of Science ®Google Scholar
• Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009;122(Pt 20):3589–3594.
   PubMed Web of Science ®Google Scholar
• Isakov N, Altman A. PKC-theta-mediated signal delivery from the TCR/CD28 surface receptors. Front Immunol 2012;3:273.
   PubMed Web of Science ®Google Scholar
• Zanin-Zhorov A, Ding Y, Kumari S, Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 2010;328(5976):372–376.
   PubMed Web of Science ®Google Scholar
• Vang KB, Yang J, Pagan AJ, Cutting edge: CD28 and c-Rel-dependent pathways initiate regulatory T cell development. J Immunol 2010;184(8):4074–4077.
   Google Scholar
• Ruan Q, Kameswaran V, Tone Y, Development of Foxp3(+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 2009;31(6):932–940.
   PubMed Web of Science ®Google Scholar
• Loizou L, Andersen KG, Betz AG. Foxp3 interacts with c-Rel to mediate NF-kappaB repression. PLoS One 2011;6(4):e18670.
   Google Scholar
• Oh-Hora M, Komatsu N, Pishyareh M, Agonist-Selected T Cell Development Requires Strong T Cell Receptor Signaling and Store-Operated Calcium Entry. Immunity 2013;38(5):881–895.
   Google Scholar
• Cipolletta D, Feuerer M, Li A, PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 2012;486(7404):549–553.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• Nie H, Zheng Y, Li R, Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat Med 2013;19(3):322–328.
   PubMed Web of Science ®Google Scholar
• Frauwirth KA, Riley JL, Harris MH, The CD28 signaling pathway regulates glucose metabolism. Immunity 2002;16(6):769–777.
   PubMed Web of Science ®Google Scholar
• Jacobs SR, Herman CE, Maciver NJ, Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 2008;180(7):4476–4486.
   PubMed Web of Science ®Google Scholar
• 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.
   Google Scholar
• Parry RV, Chemnitz JM, Frauwirth KA, CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25(21):9543–9553.
   PubMed Web of Science ®Google Scholar
• Reissig S, Hovelmeyer N, Weigmann B, The tumor suppressor CYLD controls the function of murine regulatory T cells. J Immunol 2012;189(10):4770–4776.
   PubMed Web of Science ®Google Scholar
• Chang JH, Xiao Y, Hu H, 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.
   Google Scholar
• Zorn E, Nelson EA, Mohseni M, IL-2 regulates FOXP3 expression in human CD4+CD25 +regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 2006;108(5):1571–1579.
   PubMed Web of Science ®Google Scholar
• Boyman O, Krieg C, Letourneau S, 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.
   PubMed Web of Science ®Google Scholar
• Garg G, Tyler JR, Yang JH, 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.
   PubMed Web of Science ®Google Scholar
• Tanaka K, Ichiyama K, Hashimoto M, Loss of suppressor of cytokine signaling 1 in helper 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.
   PubMed Web of Science ®Google Scholar
• Takahashi R, Nishimoto S, Muto G, 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Amendola M, Passerini L, Pucci F, Regulated and multiple miRNA and siRNA delivery into primary cells by a lentiviral platform. Mol Ther 2009;17(6):1039–1052.
   Google Scholar
• Zhou X, Bailey-Bucktrout SL, Jeker LT, Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009;10(9):1000–1007.
   PubMed Web of Science ®Google Scholar
• Miyao T, Floess S, Setoguchi R, 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.
   PubMed Web of Science ®Google Scholar
• Kanhere A, Hertweck A, Bhatia U, T-bet and GATA3 orchestrate Th1 and Th2 differentiation through lineage-specific targeting of distal regulatory elements. Nature Commun 2012;3:1268.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Duhen T, Duhen R, Lanzavecchia A, et al. Functionally distinct subsets of human FOXP3+ Treg cells that phenotypically mirror effector Th cells. Blood 2012;119(19):4430–4440.
   PubMed Web of Science ®Google Scholar
• Wei J, Duramad O, Perng OA, 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.
   PubMed Web of Science ®Google Scholar
• Sawitzki B, Kingsley CI, Oliveira V, IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med 2005;201(12):1925–1935.
   Google Scholar
• Koenecke C, Lee CW, Thamm K, 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.
   Google Scholar
• Koch MA, Thomas KR, Perdue NR, T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 2012;37(3):501–510.
   Google Scholar
• Hall AO, Beiting DP, Tato C, The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 2012;37(3):511–523.
   PubMed Web of Science ®Google Scholar
• Dominguez-Villar M, Baecher-Allan CM, Hafler DA. Identification of T helper type 1-like, Foxp3 +regulatory T cells in human autoimmune disease. Nat Med 2011;17(6):673–675.
   PubMed Web of Science ®Google Scholar
• McClymont SA, Putnam AL, Lee MR, Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol 2011;186(7):3918–3926.
   PubMed Web of Science ®Google Scholar
• Mantel PY, Kuipers H, Boyman O, GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol 2007;5(12):2847–2861.
   Google Scholar
• Kim BS, Kim IK, Park YJ, 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.
   PubMedGoogle Scholar
• Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007;445(7129):766–770.
   PubMed Web of Science ®Google Scholar
• Hansmann L, Schmidl C, Kett J, Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression. J Immunol 2012;188(3):1275–1282.
   Google Scholar
• Zheng Y, Chaudhry A, Kas A, Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009;458(7236):351–356.
   Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Wohlfert EA, Grainger JR, Bouladoux N, GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J Clin Invest 2011;121(11):4503–4515.
   Google Scholar
• Krishnamoorthy N, Khare A, Oriss TB, Early infection with respiratory syncytial virus impairs regulatory T cell function and increases susceptibility to allergic asthma. Nat Med 2012;18(10):1525–1530.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Ichiyama K, Yoshida H, Wakabayashi Y, Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat. J Biol Chem 2008; 283(25):17003–17008.
   PubMed Web of Science ®Google Scholar
• Jeron A, Hansen W, Ewert F, 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.
   Google Scholar
• Burgler S, Mantel PY, Bassin C, RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter. J Immunol 2010;184(11):6161–6169.
   Google Scholar
• Passerini L, Olek S, Di Nunzio S, 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.
   Google Scholar
• Tartar DM, VanMorlan AM, Wan X, FoxP3+RORgammat+ T helper intermediates display suppressive function against autoimmune diabetes. J Immunol 2010;184(7):3377–3385.
   Google Scholar
• Koenen HJ, Smeets RL, Vink PM, Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008;112(6):2340–2352.
   PubMed Web of Science ®Google Scholar
• Miyara M, Yoshioka Y, Kitoh A, Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30(6):899–911.
   PubMed Web of Science ®Google Scholar
• McMurchy AN, Gillies J, Gizzi MC, A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells. Blood 2013;121(8):1265–1275.
   Google Scholar
• Chaudhry A, Rudra D, Treuting P, CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 2009;326(5955):986–991.
   Web of Science ®Google Scholar
• Yu D, Rao S, Tsai LM, The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 2009;31(3):457–468.
   PubMed Web of Science ®Google Scholar
• Nurieva RI, Chung Y, Martinez GJ, Bcl6 mediates the development of T follicular helper cells. Science 2009;325(5943):1001–1005.
   PubMed Web of Science ®Google Scholar
• Linterman MA, Pierson W, Lee SK, Foxp3+ follicular regulatory T cells control the germinal center response. Nat Med 2011;17(8):975–982.
   PubMed Web of Science ®Google Scholar
• Chung Y, Tanaka S, Chu F, Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat Med 2011;17(8):983–988.
   PubMed Web of Science ®Google Scholar
• Wollenberg I, Agua-Doce A, Hernandez A, Regulation of the germinal center reaction by Foxp3+ follicular regulatory T cells. J Immunol 2011;187(9):4553–4560.
   PubMed Web of Science ®Google Scholar
• Sawant DV, Sehra S, Nguyen ET, Bcl6 controls the Th2 inflammatory activity of regulatory T cells by repressing Gata3 function. J Immunol 2012;189(10):4759–4769.
   Google Scholar
• Martins GA, Cimmino L, Shapiro-Shelef M, Transcriptional repressor Blimp-1 regulates T cell homeostasis and function. Nat Immunol 2006;7(5):457–465.
   PubMed Web of Science ®Google Scholar
• Cretney E, Xin A, Shi W, 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.
   PubMed Web of Science ®Google Scholar
• Thornton AM, Korty PE, Tran DQ, 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.
   PubMed Web of Science ®Google Scholar
• Richards EJ. Inherited epigenetic variation–revisiting soft inheritance. Nat Rev Genet 2006;7(5):395–401.
   PubMed Web of Science ®Google Scholar
• Schmidl C, Klug M, Boeld TJ, Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 2009;19(7):1165–1174.
   PubMed Web of Science ®Google Scholar
• Tian Y, Jia Z, Wang J, Global mapping of H3K4me1 and H3K4me3 reveals the chromatin state-based cell type-specific gene regulation in human Treg cells. PLoS One 2011;6(11):e27770.
   PubMed Web of Science ®Google Scholar
• Floess S, Freyer J, Siewert C, Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007;5(2):e38.
   PubMed Web of Science ®Google Scholar
• Ohkura N, Hamaguchi M, Morikawa H, 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.
   PubMed Web of Science ®Google Scholar
• Samstein RM, Arvey A, Josefowicz SZ, Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012;151(1):153–166.
   PubMed Web of Science ®Google Scholar
• Holmes D, Gao J, Su L. Foxp3 inhibits HDAC1 activity to modulate gene expression in human T cells. Virology 2011;421(1):12–18.
   Google Scholar
• Katoh H, Qin ZS, Liu R, 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.
   Google Scholar
• Pan F, Yu H, Dang EV, Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 2009;325(5944):1142–1146.
   PubMed Web of Science ®Google Scholar
• Bettini ML, Pan F, Bettini M, Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity 2012;36(5):717–730.
   PubMed Web of Science ®Google Scholar
• Mackey-Cushman SL, Gao J, Holmes DA, FoxP3 interacts with linker histone H1.5 to modulate gene expression and program Treg cell activity. Genes Immun 2011;12(7):559–567.
   Google Scholar