Lineage stability and phenotypic plasticity of Foxp3+ regulatory T cells

Immunological Reviews

Volumn 259, Issue 1, 2014, Pages 159-172

  Hori, Shohei ^a  

^a Institute of Physical and Chemical Research   (Japan)

Author keywords

Cell fate determination; Epigenetic memory; Foxp3; Heterogeneity; Phenotypic plasticity; Regulatory T cells

Indexed keywords

GAMMA INTERFERON; INTERLEUKIN 12; INTERLEUKIN 17; INTERLEUKIN 2; INTERLEUKIN 4; INTERLEUKIN 6; TRANSCRIPTION FACTOR FOXP3;

ARTICLE; AUTOIMMUNE DISEASE; CELL FATE; CELL HETEROGENEITY; CELL LINEAGE; CELLULAR IMMUNITY; CYTOKINE RESPONSE; DNA METHYLATION; DNA SEQUENCE; EPIGENETICS; FOXP3 REGULATORY T LYMPHOCYTE; GRAFT VERSUS HOST REACTION; HELPER CELL; HUMAN; IMMUNOLOGICAL TOLERANCE; LYMPHOCYTE DIFFERENTIATION; NONHUMAN; PHENOTYPIC PLASTICITY; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TH17 CELL;

CELL FATE DETERMINATION; EPIGENETIC MEMORY; FOXP3; HETEROGENEITY; PHENOTYPIC PLASTICITY; REGULATORY T CELLS;

ANIMALS; CELL DIFFERENTIATION; CELL LINEAGE; EPIGENESIS, GENETIC; FORKHEAD TRANSCRIPTION FACTORS; HOMEOSTASIS; HUMANS; IMMUNOLOGIC MEMORY; PHENOTYPE; T-LYMPHOCYTES, REGULATORY;

EID: 84897944747     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/imr.12175     Document Type: Article

References (129)

1. Le Douarin N, et al. Evidence for a thymus-dependent form of tolerance that is not based on elimination or anergy of reactive T cells. Immunol Rev 1996;149:35-53.
2. Modigliani Y, Bandeira A, Coutinho A. A model for developmentally acquired thymus-dependent tolerance to central and peripheral antigens. Immunol Rev 1996;149:155-120.
3. Saoudi A, Seddon B, Heath V, Fowell D, Mason D. The physiological role of regulatory T cells in the prevention of autoimmunity: the function of the thymus in the generation of the regulatory T cell subset. Immunol Rev 1996;149:195-216.
4. Cobbold SP, Adams E, Marshall SE, Davies JD, Waldmann H. Mechanisms of peripheral tolerance and suppression induced by monoclonal antibodies to CD4 and CD8. Immunol Rev 1996;149:5-33.
5. Singh B, et al. Control of intestinal inflammation by regulatory T cells. Immunol Rev 2001;182:190-200.
6. Furtado GC, Olivares-Villagomez D, Curotto de Lafaille MA, Wensky AK, Latkowski JA, Lafaille JJ. Regulatory T cells in spontaneous autoimmune encephalomyelitis. Immunol Rev 2001;182:122-134.
7. Sakaguchi S, et al. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001;182:18-32.
8. Shevach EM, McHugh RS, Piccirillo CA, Thornton AM. Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev 2001;182:58-67.
9. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003;299:1057-1061.
10. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-336.
11. Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003;4:337-342.
12. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005;22:329-341.
13. Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007;8:191-197.
14. Lahl K, et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 2007;204:57-63.
15. Kim J, et al. Cutting edge: depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice. J Immunol 2009;183:7631-7634.
16. Sakaguchi S, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 2006;212:8-27.
17. Demengeot J, Zelenay S, Moraes-Fontes MF, Caramalho I, Coutinho A. Regulatory T cells in microbial infection. Springer Semin Immunopathol 2006;28:41-50.
18. Belkaid Y, Tarbell K. Regulatory T cells in the control of host-microorganism interactions (*). Annu Rev Immunol 2009;27:551-589.
19. Izcue A, Coombes JL, Powrie F. Regulatory lymphocytes and intestinal inflammation. Annu Rev Immunol 2009;27:313-338.
20. Bilate AM, Lafaille JJ. Induced CD4+Foxp3+ regulatory T cells in immune tolerance. Annu Rev Immunol 2012;30:733-758.
21. Nagano Y, Itoh K, Honda K. The induction of Treg cells by gut-indigenous Clostridium. Curr Opin Immunol 2012;24:392-397.
22. Nutsch KM, Hsieh CS. T cell tolerance and immunity to commensal bacteria. Curr Opin Immunol 2012;24:385-391.
23. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 2004;5:266-271.
24. Waldmann H, Adams E, Fairchild P, Cobbold S. Infectious tolerance and the long-term acceptance of transplanted tissue. Immunol Rev 2006;212:301-313.
25. Yamaguchi T, Sakaguchi S. Regulatory T cells in immune surveillance and treatment of cancer. Semin Cancer Biol 2006;16:115-123.
26. Burzyn D, Benoist C, Mathis D. Regulatory T cells in nonlymphoid tissues. Nat Immunol 2013;14:1007-1013.
27. Hori S. Stability of regulatory T-cell lineage. Adv Immunol 2011;112:1-24.
28. Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012;30:531-564.
29. Campbell DJ, Koch MA. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 2011;11:119-130.
30. Zhou X, Bailey-Bucktrout S, Jeker LT, Bluestone JA. Plasticity of CD4(+) FoxP3(+) T cells. Curr Opin Immunol 2009;21:281-285.
31. Mellor AL, Munn DH. Physiologic control of the functional status of Foxp3+ regulatory T cells. J Immunol 2011;186:4535-4540.
32. Liston A, Piccirillo CA. Developmental plasticity of murine and human Foxp3(+) regulatory T cells. Adv Immunol 2013;119:85-106.
33. Bailey-Bucktrout SL, Bluestone JA. Regulatory T cells: stability revisited. Trends Immunol 2011;32:301-306.
34. Hori S. Regulatory T cell plasticity: beyond the controversies. Trends Immunol 2011;32:295-300.
35. Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H. The plasticity and stability of regulatory T cells. Nat Rev Immunol 2013;13:461-467.
36. Riley JL, June CH, Blazar BR. Human T regulatory cell therapy: take a billion or so and call me in the morning. Immunity 2009;30:656-665.
37. Edinger M, Hoffmann P. Regulatory T cells in stem cell transplantation: strategies and first clinical experiences. Curr Opin Immunol 2011;23:679-684.
38. 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 mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151-1164.
39. Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of developmental abnormality of a T cell subpopulation. J Exp Med 1996;184:387-396.
40. Itoh M, et al. Thymus and autoimmunity: production of CD25+CD4+ naturally anergic and suppressive T cells as a key function of the thymus in maintaining immunologic self-tolerance. J Immunol 1999;162:5317-5326.
41. Stephens LA, Mason D. CD25 is a marker for CD4+ thymocytes that prevent autoimmune diabetes in rats, but peripheral T cells with this function are found in both CD25+ and CD25- subpopulations. J Immunol 2000;165:3105-3110.
42. Jordan MS, et al. Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2001;2:301-306.
43. Apostolou I, Sarukhan A, Klein L, von Boehmer H. Origin of regulatory T cells with known specificity for antigen. Nat Immunol 2002;3:756-763.
44. Kawahata K, et al. Generation of CD4(+)CD25(+) regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression. J Immunol 2002;168:4399-4405.
45. Hsieh CS, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 2004;21:267-277.
46. Hsieh CS, Zheng Y, Liang Y, Fontenot JD, Rudensky AY. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006;7:401-410.
47. Annacker O, Burlen-Defranoux O, Pimenta-Araujo R, Cumano A, Bandeira A. Regulatory CD4 T cells control the size of the peripheral activated/memory CD4 T cell compartment. J Immunol 2000;164:3573-3580.
48. Gavin MA, Clarke SR, Negrou E, Gallegos A, Rudensky A. Homeostasis and anergy of CD4(+)CD25(+) suppressor T cells in vivo. Nat Immunol 2002;3:33-41.
49. Fisson S, et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med 2003;198:737-746.
50. Klein L, Khazaie K, von Boehmer H. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci USA 2003;100:8886-8891.
51. Chen W, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003;198:1875-1886.
52. Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010;463:808-812.
53. Floess S, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007;5:e38.
54. Huehn J, Polansky JK, Hamann A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage? Nat Rev Immunol 2009;9:83-89.
55. Polansky JK, et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol 2008;38:1654-1663.
56. Weiss JM, et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J Exp Med 2012;209:1723-1742, s1721.
57. Gavin MA, 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;103:6659-6664.
58. Allan SE, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol 2007;19:345-354.
59. 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;110:2983-2990.
60. Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol 2007;37:129-138.
61. Miyara M, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911.
62. Gavin MA, et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 2007;445:771-775.
63. Lin W, et al. Regulatory T cell development in the absence of functional Foxp3. Nat Immunol 2007;8:359-368.
64. Ohkura N, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 2012;37:785-799.
65. Hill JA, et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 2007;27:786-800.
66. Fu W, et al. A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells. Nat Immunol 2012;13:972-980.
67. Rudra D, et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 2012;13:1010-1019.
68. Samstein RM, et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012;151:153-166.
69. Komatsu N, Mariotti-Ferrandiz ME, Wang Y, Malissen B, Waldmann H, Hori S. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci USA 2009;106:1903-1908.
70. Duarte JH, Zelenay S, Bergman ML, Martins AC, Demengeot J. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur J Immunol 2009;39:948-955.
71. Yurchenko E, et al. Inflammation-driven reprogramming of CD4+ Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo. PLoS ONE 2012;7:e35572.
72. Tsuji M, et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 2009;323:1488-1492.
73. Murai M, et al. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 2009;10:1178-1184.
74. 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.
75. Yang XO, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008;29:44-56.
76. Wei G, et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 2009;30:155-167.
77. 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;17:673-675.
78. Koch MA, Thomas KR, Perdue NR, Smigiel KS, Srivastava S, Campbell DJ. T-bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 2012;37:501-510.
79. Zhao J, Zhao J, Perlman S. Differential effects of IL-12 on Tregs and non-Treg T cells: roles of IFN-gamma, IL-2 and IL-2R. PLoS ONE 2012;7:e46241.
80. Gabrysova L, Christensen JR, Wu X, Kissenpfennig A, Malissen B, O'Garra A. Integrated T-cell receptor and costimulatory signals determine TGF-beta-dependent differentiation and maintenance of Foxp3+ regulatory T cells. Eur J Immunol 2011;41:1242-1248.
81. Vu MD, et al. OX40 costimulation turns off Foxp3+ Tregs. Blood 2007;110:2501-2510.
82. Degauque N, et al. Immunostimulatory Tim-1-specific antibody deprograms Tregs and prevents transplant tolerance in mice. J Clin Invest 2008;118:735-741.
83. Hoffmann P, et al. Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur J Immunol 2009;39:1088-1097.
84. Koenen HJ, Smeets RL, Vink PM, van Rijssen E, Boots AM, Joosten I. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008;112:2340-2352.
85. Miyao T, et al. Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012;36:262-275.
86. Zhou X, et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 2009;10:1000-1007.
87. Bailey-Bucktrout SL, et al. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 2013;39:949-962.
88. Osorio F, et al. DC activated via dectin-1 convert Treg into IL-17 producers. Eur J Immunol 2008;38:3274-3281.
89. Beriou G, et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 2009;113:4240-4249.
90. Voo KS, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci USA 2009;106:4793-4798.
91. Zhou L, et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008;453:236-240.
92. Oldenhove G, et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 2009;31:772-786.
93. Zhao J, Fett C, Trandem K, Fleming E, Perlman S. IFN-{gamma}- and IL-10-expressing virus epitope-specific Foxp3+ T reg cells in the central nervous system during encephalomyelitis. J Exp Med 2011;208:1571-1577.
94. McClymont SA, et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol 2011;186:3918-3926.
95. Sharma MD, et al. Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 2010;33:942-954.
96. Sharma MD, et al. An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 2013;38:998-1012.
97. Mottet C, Uhlig HH, Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 2003;170:3939-3943.
98. Liu X, et al. T cell receptor CDR3 sequence but not recognition characteristics distinguish autoreactive effector and Foxp3(+) regulatory T cells. Immunity 2009;31:909-920.
99. Rubtsov YP, et al. Stability of the regulatory T cell lineage in vivo. Science 2010;329:1667-1671.
100. Hori S. Developmental plasticity of Foxp3+ regulatory T cells. Curr Opin Immunol 2010;22:575-582.
101. Zelenay S, Lopes-Carvalho T, Caramalho I, Moraes-Fontes MF, Rebelo M, Demengeot J. Foxp3+ CD25- CD4 T cells constitute a reservoir of committed regulatory cells that regain CD25 expression upon homeostatic expansion. Proc Natl Acad Sci USA 2005;102:4091-4096.
102. Almeida AR, Zaragoza B, Freitas AA. Competition controls the rate of transition between the peripheral pools of CD4+CD25- and CD4+CD25+ T cells. Int Immunol 2006;18:1607-1613.
103. Schlenner SM, et al. Fate mapping reveals separate origins of T cells and myeloid lineages in the thymus. Immunity 2010;32:426-436.
104. Kim HP, Leonard WJ. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 2007;204:1543-1551.
105. Polansky JK, et al. Methylation matters: binding of Ets-1 to the demethylated Foxp3 gene contributes to the stabilization of Foxp3 expression in regulatory T cells. J Mol Med 2010;88:1029-1040.
106. Laurence A, et al. STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 2012;37:209-222.
107. Chen Z, et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 2013;39:272-285.
108. van Loosdregt J, et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 2013;39:259-271.
109. Liu H, Komai-Koma M, Xu D, Liew FY. Toll-like receptor 2 signaling modulates the functions of CD4+ CD25+ regulatory T cells. Proc Natl Acad Sci USA 2006;103:7048-7053.
110. d'Hennezel E, Yurchenko E, Sgouroudis E, Hay V, Piccirillo CA. Single-cell analysis of the human T regulatory population uncovers functional heterogeneity and instability within FOXP3+ cells. J Immunol 2011;186:6788-6797.
111. Sawitzki B, Kingsley CI, Oliveira V, Karim M, Herber M, Wood KJ. IFN-gamma production by alloantigen-reactive regulatory T cells is important for their regulatory function in vivo. J Exp Med 2005;201:1925-1935.
112. Koenecke C, et al. IFN-gamma production by allogeneic Foxp3+ regulatory T cells is essential for preventing experimental graft-versus-host disease. J Immunol 2012;189:2890-2896.
113. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002;196:389-399.
114. McGeachy MJ, et al. 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 2007;8:1390-1397.
115. Esplugues E, et al. Control of TH17 cells occurs in the small intestine. Nature 2011;475:514-518.
116. Heit A, et al. Circumvention of regulatory CD4(+) T cell activity during cross-priming strongly enhances T cell-mediated immunity. Eur J Immunol 2008;38:1585-1597.
117. Klages K, et al. Selective depletion of Foxp3+ regulatory T cells improves effective therapeutic vaccination against established melanoma. Cancer Res 2010;70:7788-7799.
118. Pace L, et al. Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science 2012;338:532-536.
119. Lund JM, Hsing L, Pham TT, Rudensky AY. Coordination of early protective immunity to viral infection by regulatory T cells. Science 2008;320:1220-1224.
120. Burchill MA, et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 2008;28:112-121.
121. Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity 2008;28:100-111.
122. Wirnsberger G, Mair F, Klein L. Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control. Proc Natl Acad Sci USA 2009;106:10278-10283.
123. Schallenberg S, Tsai PY, Riewaldt J, Kretschmer K. Identification of an immediate Foxp3(-) precursor to Foxp3(+) regulatory T cells in peripheral lymphoid organs of nonmanipulated mice. J Exp Med 2010;207:1393-1407.
124. Tai X, et al. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 2013;38:1116-1128.
125. Toker A, et al. Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J Immunol 2013;190:3180-3188.
126. Hori S. The Foxp3 interactome: a network perspective of T(reg) cells. Nat Immunol 2012;13:943-945.
127. Enver T, Pera M, Peterson C, Andrews PW. Stem cell states, fates, and the rules of attraction. Cell Stem Cell 2009;4:387-397.
128. Macarthur BD, Ma'ayan A, Lemischka IR. Systems biology of stem cell fate and cellular reprogramming. Nat Rev Mol Cell Biol 2009;10:672-681.
129. Huang S. Systems biology of stem cells: three useful perspectives to help overcome the paradigm of linear pathways. Philos Trans R Soc Lond B Biol Sci 2011;366:2247-2259.