Epigenetic and transcriptional control of Foxp3+ regulatory T cells

Seminars in Immunology

Volumn 27, Issue 1, 2015, Pages 10-18

  Huehn, Jochen ^a   Beyer, Marc ^b  

^a HELMHOLTZ CENTRE FOR INFECTION RESEARCH   (Germany)

^b UNIVERSITY OF BONN   (Germany)

Author keywords

Epigenetic regulation; Foxp3; Immunoregulation; Regulatory T cells

Indexed keywords

TRANSCRIPTION FACTOR FOXP3; FORKHEAD TRANSCRIPTION FACTOR;

CELL MATURATION; EPIGENETICS; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; NONHUMAN; PHENOTYPE; REGULATORY T LYMPHOCYTE; REVIEW; THYMUS; ANIMAL; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; IMMUNOLOGICAL TOLERANCE; IMMUNOLOGY; METABOLISM;

ANIMALS; EPIGENESIS, GENETIC; FORKHEAD TRANSCRIPTION FACTORS; GENE EXPRESSION REGULATION; HUMANS; IMMUNE TOLERANCE; T-LYMPHOCYTES, REGULATORY; TRANSCRIPTION, GENETIC;

EID: 84928700441     PISSN: 10445323     EISSN: 10963618     Source Type: Journal    
DOI: 10.1016/j.smim.2015.02.002     Document Type: Review

References (119)

1. Sakaguchi S., Yamaguchi T., Nomura T., Ono M. Regulatory T cells and immune tolerance. Cell 2008, 133:775-787.
2. Josefowicz S.Z., Lu L.F., Rudensky A.Y. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012, 30:531-564.
3. + T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol 1993, 5:1461-1471.
4. Sakaguchi S., Sakaguchi N., Asano M., Itoh M., Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995, 155:1151-1164.
5. 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.
6. Shevach E.M. Regulatory T cells in autoimmmunity. Annu Rev Immunol 2000, 18:423-449.
7. + regulatory T cells. Nat Immunol 2003, 4:330-336.
8. Hori S., Nomura T., Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 2003, 299:1057-1061.
9. + T regulatory cells. Nat Immunol 2003, 4:337-342.
10. Hsieh C.S., Lee H.M., Lio C.W. Selection of regulatory T cells in the thymus. Nat Rev Immunol 2012, 12:157-167.
11. + regulatory T cells: more of the same or a division of labor?. Immunity 2009, 30:626-635.
12. Haribhai D., Williams J.B., Jia S., Nickerson D., Schmitt E.G., Edwards B., et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 2011, 35:109-122.
13. Cording S., Wahl B., Kulkarni D., Chopra H., Pezoldt J., Buettner M., et al. The intestinal micro-environment imprints stromal cells to promote efficient Treg induction in gut-draining lymph nodes. Mucosal Immunol 2014, 7:359-368.
14. + regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 2008, 29:114-126.
15. Kerdiles Y.M., Stone E.L., Beisner D.R., McGargill M.A., Ch'en I.L., Stockmann C., et al. Foxo transcription factors control regulatory T cell development and function. Immunity 2010, 33:890-904.
16. + regulatory T cells in immune tolerance. Annu Rev Immunol 2012, 30:733-758.
17. Lathrop S.K., Bloom S.M., Rao S.M., Nutsch K., Lio C.W., Santacruz N., et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 2011, 478:250-254.
18. + regulatory T cells in the lamina propria. Immunity 2011, 34:237-246.
19. Josefowicz S.Z., Niec R.E., Kim H.Y., Treuting P., Chinen T., Zheng Y., et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 2012, 482:395-399.
20. Samstein R.M., Josefowicz S.Z., Arvey A., Treuting P.M., Rudensky A.Y. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell 2012, 150:29-38.
21. Abbas A.K., Benoist C., Bluestone J.A., Campbell D.J., Ghosh S., Hori S., et al. Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 2013, 14:307-308.
22. + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003, 198:1875-1886.
23. Williams L.M., Rudensky A.Y. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 2007, 8:277-284.
24. Zheng Y., Rudensky A.Y. Foxp3 in control of the regulatory T cell lineage. Nat Immunol 2007, 8:457-462.
25. + regulatory T cells induces a scurfy-like disease. J Exp Med 2007, 204:57-63.
26. Kim J.M., Rasmussen J.P., Rudensky A.Y., Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol 2007, 8:191-197.
27. Ramsdell F., Ziegler S.F. FOXP3 and scurfy: how it all began. Nat Rev Immunol 2014, 14:343-349.
28. Li B., Samanta A., Song X., Iacono K.T., Brennan P., Chatila T.A., 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, 19:825-835.
29. Li B., Samanta A., Song X., Iacono K.T., Bembas K., Tao R., et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc Natl Acad Sci U S A 2007, 104:4571-4576.
30. Bettini M.L., Pan F., Bettini M., Finkelstein D., Rehg J.E., Floess S., et al. Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity 2012, 36:717-730.
31. Rudra D., deRoos P., Chaudhry A., Niec R.E., Arvey A., Samstein R.M., et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol 2012, 13:1010-1019.
32. Samstein R.M., Arvey A., Josefowicz S.Z., Peng X., Reynolds A., Sandstrom R., et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 2012, 151:153-166.
33. Sadlon T.J., Wilkinson B.G., Pederson S., Brown C.Y., Bresatz S., Gargett T., et al. Genome-wide identification of human FOXP3 target genes in natural regulatory T cells. J Immunol 2010, 185:1071-1081.
34. Marson A., Kretschmer K., Frampton G.M., Jacobsen E.S., Polansky J.K., MacIsaac K.D., et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 2007, 445:931-935.
35. Zheng Y., Josefowicz S.Z., Kas A., Chu T.T., Gavin M.A., Rudensky A.Y. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 2007, 445:936-940.
36. Jaenisch R., Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 2003, 33(Suppl.):245-254.
37. Greer E.L., Shi Y. Histone methylation: a dynamic mark in health, disease and inheritance. Nat Rev Genet 2012, 13:343-357.
38. Smith Z.D., Meissner A. DNA methylation: roles in mammalian development. Nat Rev Genet 2013, 14:204-220.
39. Zaret K.S., Carroll J.S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev 2011, 25:2227-2241.
40. Kitagawa Y., Ohkura N., Sakaguchi S. Epigenetic control of thymic Treg-cell development. Eur J Immunol 2015, 45:11-16.
41. Ohkura N., Kitagawa Y., Sakaguchi S. Development and maintenance of regulatory T cells. Immunity 2013, 38:414-423.
42. Ohkura N., Hamaguchi M., Morikawa H., Sugimura K., Tanaka A., Ito Y., 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.
43. Mantel P.Y., Ouaked N., Ruckert B., Karagiannidis C., Welz R., Blaser K., et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J Immunol 2006, 176:3593-3600.
44. Tone Y., Furuuchi K., Kojima Y., Tykocinski M.L., Greene M.I., Tone M. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat Immunol 2008, 9:194-202.
45. Kim H.P., Leonard W.J. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J Exp Med 2007, 204:1543-1551.
46. Zheng Y., Josefowicz S., Chaudhry A., Peng X.P., Forbush K., Rudensky A.Y. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 2010, 463:808-812.
47. Janson P.C., Winerdal M.E., Marits P., Thorn M., Ohlsson R., Winqvist O. FOXP3 promoter demethylation reveals the committed Treg population in humans. PLoS ONE 2008, 3:e1612.
48. Liu B., Tahk S., Yee K.M., Fan G., Shuai K. The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science 2010, 330:521-525.
49. Rudra D., Egawa T., Chong M.M., Treuting P., Littman D.R., Rudensky A.Y. Runx-CBFbeta complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nat Immunol 2009, 10:1170-1177.
50. Sekiya T., Kashiwagi I., Yoshida R., Fukaya T., Morita R., Kimura A., et al. Nr4a receptors are essential for thymic regulatory T cell development and immune homeostasis. Nat Immunol 2013, 14:230-237.
51. Xiong Y., Khanna S., Grzenda A.L., Sarmento O.F., Svingen P.A., Lomberk G.A., et al. Polycomb antagonizes p300/CREB-binding protein-associated factor to silence FOXP3 in a Kruppel-like factor-dependent manner. J Biol Chem 2012, 287:34372-34385.
52. Schlenner S.M., Weigmann B., Ruan Q., Chen Y., von Boehmer H. Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut. J Exp Med 2012, 209:1529-1535.
53. Weiss J.M., Bilate A.M., Gobert M., Ding Y., Curotto de Lafaille M.A., Parkhurst C.N., 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.
54. + T cells. Nat Commun 2011, 2:269.
55. Xu L., Kitani A., Stuelten C., McGrady G., Fuss I., Strober W. Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 2010, 33:313-325.
56. Floess S., Freyer J., Siewert C., Baron U., Olek S., Polansky J., et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 2007, 5:e38.
57. Huehn J., Polansky J.K., Hamann A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T-cell lineage?. Nat Rev Immunol 2009, 9:83-89.
58. Polansky J.K., Kretschmer K., Freyer J., Floess S., Garbe A., Baron U., et al. DNA methylation controls Foxp3 gene expression. Eur J Immunol 2008, 38:1654-1663.
59. Toker A., Engelbert D., Garg G., Polansky J.K., Floess S., Miyao T., 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.
60. +T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 2012, 36:262-275.
61. Nair V.S., Oh K.I. Down-regulation of Tet2 prevents TSDR demethylation in IL2 deficient regulatory T cells. Biochem Biophys Res Commun 2014, 450:918-924.
62. Wang L., Liu Y., Han R., Beier U.H., Thomas R.M., Wells A.D., et al. Mbd2 promotes foxp3 demethylation and T-regulatory-cell function. Mol Cell Biol 2013, 33:4106-4115.
63. Josefowicz S.Z., Wilson C.B., Rudensky A.Y. Cutting edge: TCR stimulation is sufficient for induction of Foxp3 expression in the absence of DNA methyltransferase 1. J Immunol 2009, 182:6648-6652.
64. Zorn E., Nelson E.A., Mohseni M., Porcheray F., Kim H., Litsa D., et al. 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, 108:1571-1579.
65. Feng Y., Arvey A., Chinen T., van der Veeken J., Gasteiger G., Rudensky A.Y. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 2014, 158:749-763.
66. Li X., Liang Y., LeBlanc M., Benner C., Zheng Y. Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 2014, 158:734-748.
67. + regulatory T cells. Immunity 2009, 31:609-620.
68. Polansky J.K., Schreiber L., Thelemann C., Ludwig L., Kruger M., Baumgrass R., 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.
69. Morikawa H., Ohkura N., Vandenbon A., Itoh M., Nagao-Sato S., Kawaji H., et al. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc Natl Acad Sci U S A 2014, 111:5289-5294.
70. Schmidl C., Klug M., Boeld T.J., Andreesen R., Hoffmann P., Edinger M., et al. Lineage-specific DNA methylation in T cells correlates with histone methylation and enhancer activity. Genome Res 2009, 19:1165-1174.
71. + T cells. Immunity 2009, 30:155-167.
72. Arvey A., van der Veeken J., Samstein R.M., Feng Y., Stamatoyannopoulos J.A., Rudensky A.Y. Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat Immunol 2014.
73. Lio C.W., Hsieh C.S. A two-step process for thymic regulatory T cell development. Immunity 2008, 28:100-111.
74. Burchill M.A., Yang J., Vang K.B., Moon J.J., Chu H.H., Lio C.W., et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 2008, 28:112-121.
75. Tai X., Erman B., Alag A., Mu J., Kimura M., Katz G., et al. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity 2013.
76. Isomura I., Palmer S., Grumont R.J., Bunting K., Hoyne G., Wilkinson N., et al. c-Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J Exp Med 2009, 206:3001-3014.
77. Long M., Park S.G., Strickland I., Hayden M.S., Ghosh S. Nuclear factor-kappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 2009, 31:921-931.
78. + regulatory t cells is driven by the c-Rel enhanceosome. Immunity 2009, 31:932-940.
79. Oh-Hora M., Komatsu N., Pishyareh M., Feske S., Hori S., Taniguchi M., et al. Agonist-selected T cell development requires strong T cell receptor signaling and store-operated calcium entry. Immunity 2013, 38:881-895.
80. Fassett M.S., Jiang W., D'Alise A.M., Mathis D., Benoist C. Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion. Proc Natl Acad Sci U S A 2012, 109:3891-3896.
81. Yao Z., Kanno Y., Kerenyi M., Stephens G., Durant L., Watford W.T., et al. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 2007, 109:4368-4375.
82. + regulatory T cells. J Immunol 2007, 178:280-290.
83. Marie J.C., Letterio J.J., Gavin M., Rudensky A.Y. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med 2005, 201:1061-1067.
84. Ouyang W., Beckett O., Ma Q., Li M.O. Transforming growth factor-beta signaling curbs thymic negative selection promoting regulatory T cell development. Immunity 2010, 32:642-653.
85. + regulatory T cells. Nat Immunol 2008, 9:632-640.
86. + regulatory T cells. Nat Immunol 2010, 11:618-627.
87. Ouyang W., Liao W., Luo C.T., Yin N., Huse M., Kim M.V., et al. Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 2012, 491:554-559.
88. Vaeth M., Schliesser U., Muller G., Reissig S., Satoh K., Tuettenberg A., 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 U S A 2012, 109:16258-16263.
89. Benson M.J., Pino-Lagos K., Rosemblatt M., Noelle R.J. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 2007, 204:1765-1774.
90. Zheng S.G., Wang J.H., Stohl W., Kim K.S., Gray J.D., Horwitz D.A. TGF-beta requires CTLA-4 early after T cell activation to induce FoxP3 and generate adaptive CD4+CD25+ regulatory cells. J Immunol 2006, 176:3321-3329.
91. Delgoffe G.M., Kole T.P., Zheng Y., Zarek P.E., Matthews K.L., Xiao B., et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009, 30:832-844.
92. Sauer S., Bruno L., Hertweck A., Finlay D., Leleu M., Spivakov M., et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 2008, 105:7797-7802.
93. Ouyang W., Beckett O., Flavell R.A., Li M.O. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 2009, 30:358-371.
94. hi Cells. Immunity 2008, 29:758-770.
95. Mucida D., Park Y., Kim G., Turovskaya O., Scott I., Kronenberg M., et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007, 317:256-260.
96. Kang S.G., Lim H.W., Andrisani O.M., Broxmeyer H.E., Kim C.H. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol 2007, 179:3724-3733.
97. Davidson T.S., DiPaolo R.J., Andersson J., Shevach E.M. Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J Immunol 2007, 178:4022-4026.
98. Laurence A., Tato C.M., Davidson T.S., Kanno Y., Chen Z., Yao Z., et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007, 26:371-381.
99. Chen Q., Kim Y.C., Laurence A., Punkosdy G.A., Shevach E.M. IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J Immunol 2011, 186:6329-6337.
100. Ono M., Yaguchi H., Ohkura N., Kitabayashi I., Nagamura Y., Nomura T., et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 2007, 446:685-689.
101. Pan F., Yu H., Dang E.V., Barbi J., Pan X., Grosso J.F., et al. Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science 2009, 325:1142-1146.
102. Zhou L., Lopes J.E., Chong M.M., Ivanov I.I., Min R., Victora G.D., et al. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 2008, 453:236-240.
103. Du J., Huang C., Zhou B., Ziegler S.F. Isoform-specific inhibition of ROR alpha-mediated transcriptional activation by human FOXP3. J Immunol 2008, 180:4785-4792.
104. Wu Y., Borde M., Heissmeyer V., Feuerer M., Lapan A.D., Stroud J.C., et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006, 126:375-387.
105. Lee S.M., Gao B., Fang D. FoxP3 maintains Treg unresponsiveness by selectively inhibiting the promoter DNA-binding activity of AP-1. Blood 2008, 111:3599-3606.
106. Camperio C., Caristi S., Fanelli G., Soligo M., Del Porto P., Piccolella E. Forkhead transcription factor FOXP3 upregulates CD25 expression through cooperation with RelA/NF-kappaB. PLoS ONE 2012, 7:e48303.
107. Loizou L., Andersen K.G., Betz A.G. Foxp3 interacts with c-Rel to mediate NF-kappaB repression. PLoS ONE 2011, 6:e18670.
108. Zheng Y., Chaudhry A., Kas A., deRoos P., Kim J.M., Chu T.T., et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 2009, 458:351-356.
109. + Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor beta2. Immunity 2012, 37:501-510.
110. Koch M.A., Tucker-Heard G., Perdue N.R., Killebrew J.R., Urdahl K.B., Campbell D.J. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 2009, 10:595-602.
111. Wang Y., Su M.A., Wan Y.Y. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 2011, 35:337-348.
112. Wohlfert E.A., Grainger J.R., Bouladoux N., Konkel J.E., Oldenhove G., Ribeiro C.H., et al. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J Clin Investig 2011, 121:4503-4515.
113. Chaudhry A., Samstein R.M., Treuting P., Liang Y., Pils M.C., Heinrich J.M., et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 2011, 34:566-578.
114. + regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 2009, 326:986-991.
115. Burzyn D., Benoist C., Mathis D., Regulatory T cells in nonlymphoid tissues. Nat Immunol 2013, 14:1007-1013.
116. Feuerer M., Herrero L., Cipolletta D., Naaz A., Wong J., Nayer A., et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009, 15:930-939.
117. Cipolletta D., Feuerer M., Li A., Kamei N., Lee J., Shoelson S.E., et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 2012, 486:549-553.
118. Mueller E., Drori S., Aiyer A., Yie J., Sarraf P., Chen H., et al. Genetic analysis of adipogenesis through peroxisome proliferator-activated receptor gamma isoforms. J Biol Chem 2002, 277:41925-41930.
119. Burzyn D., Kuswanto W., Kolodin D., Shadrach Jennifer L., Cerletti M., Jang Y., et al. A special population of regulatory T cells potentiates muscle repair. Cell 2013, 155:1282-1295.