Role of cytokines in thymus- versus peripherally derived-regulatory T cell differentiation and function

Frontiers in Immunology

Volumn 4, Issue JUN, 2013, Pages

  Goldstein, Jérémie David ^a,b,c,f   Pérol, Louis ^c,d,e   Zaragoza, Bruno ^a,b,c   Baeyens, Audrey ^a,b,c   Marodon, Gilles ^a,b,c   Piaggio, Eliane ^c,d,e  

^a SORBONNE UNIVERSITÉ   (France)

^b CNRS   (France)

^c INSERM   (France)

^d PSL RESEARCH UNIVERSITY   (France)

^e INSTITUT CURIE   (France)

^f INSTITUTE FOR RESEARCH IN BIOMEDICINE   (Switzerland)

Author keywords

Foxp3; IL 2; pTreg; Regulatory T cells; TGF ; TNF ; tTreg

Indexed keywords

CD134 ANTIGEN; CYTOKINE; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 15; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR BETA; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BCL 2; SMAD3 PROTEIN; TRANSCRIPTION FACTOR FOXP3; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA;

AUTOIMMUNE DISEASE; AUTOIMMUNITY; CELL DIFFERENTIATION; HOMEOSTASIS; HUMAN; IMMUNE RESPONSE; IMMUNOTHERAPY; INFLAMMATION; LYMPHOCYTOPENIA; NONHUMAN; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; THYMUS;

EID: 84883772994     PISSN: None     EISSN: 16643224     Source Type: Journal    
DOI: 10.3389/fimmu.2013.00155     Document Type: Review

References (140)

1. 25+ regulatory T cells is indexed to the number of IL-2-producing cells. J. Immunol. 177, 192-200.
2. Biton, J., Semerano, L., Delavallee, L., Lemeiter, D., Laborie, M., Grouard-Vogel, G., et al. (2011). Interplay between TNF and regulatory T cells in a TNF-driven murine model of arthritis. J. Immunol. 186, 3899-3910. doi:10.4049/jimmunol.1003372
3. Bottini, N., Musumeci, L., Alonso, A., Rahmouni, S., Nika, K., Rostamkhani, M., et al. (2004). A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337-338. doi:10.1038/ng1323
4. Burchill, M. A., Yang, J., Vang, K. B., Moon, J. J., Chu, H. H., Lio, C. W., et al. (2008). Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28, 112-121. doi:10.1016/j.immuni.2007.11.022
5. 5 activation is required for the development of Foxp3(regulatory T cells. J. Immunol. 178, 280-290.
6. Chan, A. C., and Carter, P. J. (2010). Therapeutic antibodies for autoimmunity and inflammation. Nat. Rev. Immunol. 10, 301-316. doi:10.1038/nri2761
7. Chen, G., and Goeddel, D. V. (2002). TNF-R1 signaling: a beautiful pathway. Science 296, 1634-1635. doi:10.1126/science.1071924
8. Chen, Q., Kim, Y. C., Laurence, A., Punkosdy, G. A., and Shevach, E. M. (2011). IL-2 controls the stability of Foxp3 expression in TGF-beta-induced Foxp3+ T cells in vivo. J. Immunol. 186, 6329-6337. doi:10.4049/jimmunol.1100061
9. Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., et al. (2003). 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. 198, 1875-1886. doi:10.1084/jem.20030152
10. Chen, X., Baumel, M., Mannel, D. N., Howard, O. M., and Oppenheim, J. J. (2007). Interaction of TNF with TNF receptor type 2 promotes expansion and function of mouse CD4+CD25+ T regulatory cells. J. Immunol. 179, 154-161.
11. Chen, X., and Oppenheim, J. J. (2010). TNF-alpha: an activator of CD4+FoxP3+TNFR2+ regulatory T cells. Curr. Dir. Autoimmun. 11, 119-134. doi:10.1159/000289201
12. Chen, X., Wu, X., Zhou, Q., Howard, O. M., Netea, M. G., and Oppenheim, J. J. (2013). TNFR2 is critical for the stabilization of the CD4+Foxp3+ regulatory T. cell phenotype in the inflammatory environment. J. Immunol. 190, 1076-1084. doi:10.4049/jimmunol.1202659
13. Chopra, M., Riedel, S. S., Biehl, M., Krieger, S., von Krosigk, V., Bauerlein, C. A., et al. (2013). Tumor necrosis factor receptor 2-dependent homeostasis of regulatory T cells as a player in TNF-induced experimental metastasis. Carcinogenesis 34, 1296-1303. doi:10.1093/carcin/bgt038
14. Coombes, J. L., Siddiqui, K. R., Arancibia-Carcamo, C. V., Hall, J., Sun, C. M., Belkaid, Y., et al. (2007). A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757-1764. doi:10.1084/jem.20070590
15. Curotto de Lafaille, M. A., and Lafaille, J. J. (2009). Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor?. Immunity 30, 626-635. doi:10.1016/j.immuni
16. Davidson, T. S., DiPaolo, R. J., Andersson, J., and Shevach, E. M. (2007). Cutting Edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 178, 4022-4026.
17. D'Cruz, L. M., and Klein, L. (2005). Development and function of agonist-induced CD25+Foxp3+ regulatory T cells in the absence of interleukin 2 signaling. Nat. Immunol. 6, 1152-1159. doi:10.1038/ni1264
18. Deepe, G. S. Jr., and Gibbons, R. S. (2008). TNF-alpha antagonism generates a population of antigen-specific CD4+CD25+ T cells that inhibit protective immunity in murine histoplasmosis. J. Immunol. 180, 1088-1097.
19. Dinh, T. N., Kyaw, T. S., Kanellakis, P., To, K., Tipping, P., Toh, B. H., et al. (2012). Cytokine therapy with interleukin-2/anti-interleukin-2 monoclonal antibody complexes expands CD4+CD25+Foxp3+ regulatory T cells and attenuates development and progression of atherosclerosis. Circulation 126, 1256-1266. doi:10.1161/CIRCULATIONAHA.112.099044
20. Duarte, J. H., Zelenay, S., Bergman, M. L., Martins, A. C., and Demengeot, J. (2009). Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur. J. Immunol. 39, 948-955. doi:10.1002/eji.200839196
21. Ehrenstein, M. R., Evans, J. G., Singh, A., Moore, S., Warnes, G., Isenberg, D. A., et al. (2004). Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J. Exp. Med. 200, 277-285. doi:10.1084/jem.20040165
22. Ertelt, J. M., Rowe, J. H., Johanns, T. M., Lai, J. C., McLachlan, J. B., and Way, S. S. (2009). Selective priming and expansion of antigen-specific Foxp3-CD4+ T cells during Listeria monocytogenes infection. J. Immunol. 182, 3032-3038. doi:10.4049/jimmunol.0803402
23. Fahlen, L., Read, S., Gorelik, L., Hurst, S. D., Coffman, R. L., Flavell, R. A., et al. (2005). T cells that cannot respond to TGF-beta escape control by CD4(+)CD25(+) regulatory T cells. J. Exp. Med. 201, 737-746. doi:10.1084/jem.20040685
24. Faustman, D., and Davis, M. (2010). TNF receptor 2 pathway: drug target for autoimmune diseases. Nat. Rev. Drug Discov. 9, 482-493. doi:10.1038/nrd3030
25. Flanders, K. C., and Roberts, A. B. (2001). "TGF-+," in Cytokine Reference, Vol. 1, eds J. J. Oppenheim and M. Feldmann (San Diego, CA: Academic Press), 719-746.
26. Floess, S., Freyer, J., Siewert, C., Baron, U., Olek, S., Polansky, J., et al. (2007). Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38. doi:10.1371/journal.pbio.0050038
27. Fontenot, J. D., Dooley, J. L., Farr, A. G., and Rudensky, A. Y. (2005a). Developmental regulation of Foxp3 expression during ontogeny. J. Exp. Med. 202, 901-906. doi:10.1084/jem.20050784
28. Fontenot, J. D., Rasmussen, J. P., Gavin, M. A., and Rudensky, A. Y. (2005b). A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6, 1142-1151. doi:10.1038/ni1263
29. Fontenot, J. D., Gavin, M. A., and Rudensky, A. Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330-336. doi:10.1038/ni904
30. Furtado, G. C., Curotto de Lafaille, M. A., Kutchukhidze, N., and Lafaille, J. J. (2002). Interleukin 2 signaling is required for CD4(+) regulatory T cell function. J. Exp. Med. 196, 851-857. doi:10.1084/jem.20020190
31. Gavin, M. A., Rasmussen, J. P., Fontenot, J. D., Vasta, V., Manganiello, V. C., Beavo, J. A., et al. (2007). Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771-775. doi:10.1038/nature05543
32. Goldstein, J. D., Balderas, R. S., and Marodon, G. (2011). Continuous activation of the CD122/STAT-5 signaling pathway during selection of antigen-specific regulatory T cells in the murine thymus. PLoS ONE 6, e19038. doi:10.1371/journal.pone.0019038
33. Gorelik, L., and Flavell, R. A. (2000). Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171-181. doi:10.1016/S1074-7613(00)80170-3
34. Goubier, A., Dubois, B., Gheit, H., Joubert, G., Villard-Truc, F., Asselin-Paturel, C., et al. (2008). Plasmacytoid dendritic cells mediate oral tolerance. Immunity 29, 464-475. doi:10.1016/j.immuni.2008.06.017
35. Grainger, J. R., Smith, K. A., Hewitson, J. P., McSorley, H. J., Harcus, Y., Filbey, K. J., et al. (2010). Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-beta pathway. J. Exp. Med. 207, 2331-2341. doi:10.1084/jem.20101074
36. Grell, M., Becke, F. M., Wajant, H., Mannel, D. N., and Scheurich, P. (1998). TNF receptor type 2 mediates thymocyte proliferation independently of TNF receptor type 1. Eur. J. Immunol. 28, 257-263. doi:10.1002/(SICI)1521-4141(199801)28:01<257::AIDIMMU257>3.0.CO;2-G
37. Grinberg-Bleyer, Y., Baeyens, A., You, S., Elhage, R., Fourcade, G., Gregoire, S., et al. (2010a). IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871-1878. doi:10.1084/jem.20100209
38. Grinberg-Bleyer, Y., Saadoun, D., Baeyens, A., Billiard, F., Goldstein, J. D., Gregoire, S., et al. (2010b). Pathogenic T cells have a paradoxical protective effect in murine autoimmune diabetes by boosting Tregs. J. Clin. Invest. 120, 4558-4568. doi:10.1172/JCI42945
39. Hamano, R., Huang, J., Yoshimura, T., Oppenheim, J. J., and Chen, X. (2011). TNF optimally activatives regulatory T cells by inducing TNF receptor superfamily members TNFR2, 4-1BB and OX40. Eur. J. Immunol. 41, 2010-2020. doi:10.1002/eji.201041205
40. Haribhai, D., Williams, J. B., Jia, S., Nickerson, D., Schmitt, E. G., Edwards, B., et al. (2011). A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 35, 109-122. doi:10.1016/j.immuni.2011.03.029
41. Haxhinasto, S., Mathis, D., and Benoist, C. (2008). The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J. Exp. Med. 205, 565-574. doi:10.1084/jem.20071477
42. Hill, J. A., Feuerer, M., Tash, K., Haxhinasto, S., Perez, J., Melamed, R., et al. (2007). Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786-800. doi:10.1016/j.immuni.2007.09.010
43. Hori, S., Nomura, T., and Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057-1061. doi:10.1126/science.1079490
44. Housley, W. J., Adams, C. O., Nichols, F. C., Puddington, L., Lingenheld, E. G., Zhu, L., et al. (2011). Natural but not inducible regulatory T cells require TNF-alpha signaling for in vivo function. J. Immunol. 186, 6779-6787. doi:10.4049/jimmunol.1003868
45. Hsieh, C. S., Zheng, Y., Liang, Y., Fontenot, J. D., and Rudensky, A. Y. (2006). An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat. Immunol. 7, 401-410. doi:10.1038/ni1318
46. Itoh, M., Takahashi, T., Sakaguchi, N., Kuniyasu, Y., Shimizu, J., Otsuka, F., et al. (1999). 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. 162, 5317-5326.
47. Jabeen, R., and Kaplan, M. H. (2012). The symphony of the ninth: the development and function of Th9 cells. Curr. Opin. Immunol. 24, 303-307. doi:10.1016/j.coi.2012.02.001
48. Jacob, C. O., and McDevitt, H. O. (1988). Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis. Nature 331, 356-358. doi:10.1038/331356a0
49. Jordan, M. S., Boesteanu, A., Reed, A. J., Petrone, A. L., Holenbeck, A. E., Lerman, M. A., et al. (2001). Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat. Immunol. 2, 301-306. doi:10.1038/86302
50. Josefowicz, S. Z., Niec, R. E., Kim, H. Y., Treuting, P., Chinen, T., Zheng, Y., et al. (2012a). Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395-399. doi:10.1038/nature10772
51. Josefowicz, S. Z., Lu, L. F., and Rudensky, A. Y. (2012b). Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531-564. doi:10.1146/annurev.immunol.25.022106.141623
52. Kaplan, D. H., Li, M. O., Jenison, M. C., Shlomchik, W. D., Flavell, R. A., and Shlomchik, M. J. (2007). Autocrine/paracrine TGFbeta1 is required for the development of epidermal Langerhans cells. J. Exp. Med. 204, 2545-2552. doi:10.1084/jem.20071401
53. Karman, J., Jiang, J. L., Gumlaw, N., Zhao, H., Campos-Rivera, J., Sancho, J., et al. (2012). Ligation of cytotoxic T lymphocyte antigen-4 to T cell receptor inhibits T cell activation and directs differentiation into Foxp3+ regulatory T cells. J. Biol. Chem. 287, 11098-11107. doi:10.1074/jbc. M111.283705
54. Kleijwegt, F. S., Laban, S., Duinkerken, G., Joosten, A. M., Zaldumbide, A., Nikolic, T., et al. (2010). Critical role for TNF in the induction of human antigen-specific regulatory T cells by tolerogenic dendritic cells. J. Immunol. 185, 1412-1418. doi:10.4049/jimmunol.1000560
55. Knoechel, B., Lohr, J., Kahn, E., Bluestone, J. A., and Abbas, A. K. (2005). Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J. Exp. Med. 202, 1375-1386. doi:10.1084/jem.20050855
56. Komatsu, N., Mariotti-Ferrandiz, M. E., Wang, Y., Malissen, B., Waldmann, H., and Hori, S. (2009). Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl. Acad. Sci. U.S.A. 106, 1903-1908. doi:10.1073/pnas.0811556106
57. Koreth, J., Matsuoka, K., Kim, H. T., McDonough, S. M., Bindra, B., Alyea, E. P. III, et al. (2011). Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365, 2055-2066. doi:10.1056/NEJMoa1108188
58. Kretschmer, K., Apostolou, I., Hawiger, D., Khazaie, K., Nussenzweig, M. C., and von Boehmer, H. (2005). Inducing and expanding regulatory T cell populations by foreign antigen. Nat. Immunol. 6, 1219-1227. doi:10.1038/ni1265
59. 5 constrains T helper 17 cell generation. Immunity 26, 371-381. doi:10.1016/j.immuni.2007.02.009
60. Leveen, P., Larsson, J., Ehinger, M., Cilio, C. M., Sundler, M., Sjostrand, L. J., et al. (2002). Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable. Blood 100, 560-568. doi:10.1182/blood. V100.2.560
61. Li, M. O., Sanjabi, S., and Flavell, R. A. (2006). Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455-471. doi:10.1016/j.immuni.2006.07.011
62. Lin, W., Haribhai, D., Relland, L. M., Truong, N., Carlson, M. R., Williams, C. B., et al. (2007). Regulatory T cell development in the absence of functional Foxp3. Nat. Immunol. 8, 359-368. doi:10.1038/ni1445
63. Lio, C. W., and Hsieh, C. S. (2008). A two-step process for thymic regulatory T cell development. Immunity 28, 100-111. doi:10.1016/j.immuni.2007.11.021
64. Liston, A., Enders, A., and Siggs, O. M. (2008). Unravelling the association of partial T-cell immunodeficiency and immune dysregulation. Nat. Rev. Immunol. 8, 545-558. doi:10.1038/nri2336
65. Liston, A., Siggs, O. M., and Goodnow, C. C. (2007). Tracing the action of IL-2 in tolerance to islet-specific antigen. Immunol. Cell Biol. 85, 338-342. doi:10.1038/sj.icb.7100049
66. Liu, V. C., Wong, L. Y., Jang, T., Shah, A. H., Park, I., Yang, X., et al. (2007). Tumor evasion of the immune system by converting CD4+CD25-T cells into CD4+CD25+ T regulatory cells: role of tumor-derived TGF-beta. J. Immunol. 178, 2883-2892.
67. Liu, Y., Zhang, P., Li, J., Kulkarni, A. B., Perruche, S., and Chen, W. (2008). A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat. Immunol. 9, 632-640. doi:10.1038/ni.1607
68. Maddur, M. S., Miossec, P., Kaveri, S. V., and Bayry, J. (2012). Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. Am. J. Pathol. 181, 8-18. doi:10.1016/j.ajpath.2012.03.044
69. Marie, J. C., Letterio, J. J., Gavin, M., and Rudensky, A. Y. (2005). TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061-1067. doi:10.1084/jem.20042276
70. Marie, J. C., Liggitt, D., and Rudensky, A. Y. (2006). Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25, 441-454. doi:10.1016/j.immuni.2006.07.012
71. Merkenschlager, M., and von Boehmer, H. (2010). PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factors. J. Exp. Med. 207, 1347-1350. doi:10.1084/jem.20101156
72. Miyao, T., Floess, S., Setoguchi, R., Luche, H., Fehling, H. J., Waldmann, H., et al. (2012). Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36, 262-275. doi:10.1016/j.immuni.2011.12.012
73. Mouly, E., Chemin, K., Nguyen, H. V., Chopin, M., Mesnard, L., Leite-de-Moraes, M., et al. (2010). The Ets-1 transcription factor controls the development and function of natural regulatory T cells. J. Exp. Med. 207, 2113-2125. doi:10.1084/jem.20092153
74. Mucida, D., Kutchukhidze, N., Erazo, A., Russo, M., Lafaille, J. J., and Curotto de Lafaille, M. A. (2005). Oral tolerance in the absence of naturally occurring Tregs. J. Clin. Invest. 115, 1923-1933. doi:10.1172/JCI24487
75. 5B mutation in diabetes pathogenesis. Ann. N. Y. Acad. Sci. 1079, 198-204. doi:10.1196/annals.1375.031
76. Nadkarni, S., Mauri, C., and Ehrenstein, M. R. (2007). Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J. Exp. Med. 204, 33-39. doi:10.1084/jem.20061531
77. Nagar, M., Jacob-Hirsch, J., Vernitsky, H., Berkun, Y., Ben-Horin, S., Amariglio, N., et al. (2010). TNF activates a NF-kappaB-regulated cellular program in human CD45RA-regulatory T cells that modulates their suppressive function. J. Immunol. 184, 3570-3581. doi:10.4049/jimmunol.0902070
78. Nie, H., Zheng, Y., Li, R., Guo, T. B., He, D., Fang, L., et al. (2013). Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis. Nat. Med. 19, 322-328. doi:10.1038/nm.3085
79. Nishikawa, H., Kato, T., Tanida, K., Hiasa, A., Tawara, I., Ikeda, H., et al. (2003). CD4+CD25+ T cells responding to serologically defined autoantigens suppress antitumor immune responses. Proc. Natl. Acad. Sci. U.S.A. 100, 10902-10906. doi:10.1073/pnas.1834479100
80. Nykjaer, A., Moller, B., Todd, R. F. III, Christensen, T., Andreasen, P. A., Gliemann, J., et al. (1994). Urokinase receptor. An activation antigen in human T lymphocytes. J. Immunol. 152, 505-516.
81. Ochando, J. C., Homma, C., Yang, Y., Hidalgo, A., Garin, A., Tacke, F., et al. (2006). Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat. Immunol. 7, 652-662. doi:10.1038/ni1333
82. Odekon, L. E., Blasi, F., and Rifkin, D. B. (1994). Requirement for receptor-bound urokinase in plasmin-dependent cellular conversion of latent TGF-beta to TGF-beta. J. Cell. Physiol. 158, 398-407. doi:10.1002/jcp.1041580303
83. Ohkura, N., Hamaguchi, M., Morikawa, H., Sugimura, K., Tanaka, A., Ito, Y., et al. (2012). T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785-799. doi:10.1016/j.immuni.2012.09.010
84. Ohkura, N., Kitagawa, Y., and Sakaguchi, S. (2013). Development and maintenance of regulatory T cells. Immunity 38, 414-423. doi:10.1016/j.immuni.2013.03.002
85. Oldenhove, G., Bouladoux, N., Wohlfert, E. A., Hall, J. A., Chou, D., Dos Santos, L., et al. (2009). Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31, 772-786. doi:10.1016/j.immuni.2009.10.001
86. 5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25-effector T cells. Int. Immunol. 20, 421-431. doi:10.1093/intimm/dxn002
87. Perez-Alvarez, R., Perez-de-Lis, M., Ramos-Casals, M., and BIOGEAS study group (2013). Biologics-induced autoimmune diseases. Curr. Opin. Rheumatol. 25, 56-64. doi:10.1097/BOR.0b013e32835b1366
88. Polansky, J. K., Kretschmer, K., Freyer, J., Floess, S., Garbe, A., Baron, U., et al. (2008). DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38, 1654-1663. doi:10.1002/eji.200838105
89. Prud'Homme, G. J. (2007). Pathobiology of transforming growth factor beta in cancer, fibrosis and immunologic disease, and therapeutic considerations. Lab. Invest. 87, 1077-1091. doi:10.1038/labinvest.3700669
90. Rauert, H., Wicovsky, A., Muller, N., Siegmund, D., Spindler, V., Waschke, J., et al. (2010). Membrane tumor necrosis factor (TNF) induces p100 processing via TNF receptor-2 (TNFR2). J. Biol. Chem. 285, 7394-7404. doi:10.1074/jbc. M109.037341
91. Robertson, S. J., Messer, R. J., Carmody, A. B., and Hasenkrug, K. J. (2006). In vitro suppression of CD8+ T cell function by Friend virus-induced regulatory T cells. J. Immunol. 176, 3342-3349.
92. Rubtsov, Y. P., Niec, R. E., Josefowicz, S., Li, L., Darce, J., Mathis, D., et al. (2010). Stability of the regulatory T cell lineage in vivo. Science 329, 1667-1671. doi:10.1126/science.1191996
93. Ruddle, N. H., Bergman, C. M., McGrath, K. M., Lingenheld, E. G., Grunnet, M. L., Padula, S. J., et al. (1990). An antibody to lymphotoxin and tumor necrosis factor prevents transfer of experimental allergic encephalomyelitis. J. Exp. Med. 172, 1193-1200. doi:10.1084/jem.172.4.1193
94. Saadoun, D., Rosenzwajg, M., Joly, F., Six, A., Carrat, F., Thibault, V., et al. (2011). Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067-2077. doi:10.1056/NEJMoa1105143
95. Sadlack, B., Lohler, J., Schorle, H., Klebb, G., Haber, H., Sickel, E., et al. (1995). Generalized autoimmune disease in interleukin-2-deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells. Eur. J. Immunol. 25, 3053-3059. doi:10.1002/eji.1830251111
96. Sadlack, B., Merz, H., Schorle, H., Schimpl, A., Feller, A. C., and Horak, I. (1993). Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253-261. doi:10.1016/0092-8674(93)80067-O
97. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M., and Toda, M. (1995). 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. 155, 1151-1164.
98. Sauer, S., Bruno, L., Hertweck, A., Finlay, D., Leleu, M., Spivakov, M., et al. (2008). T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl. Acad. Sci. U.S.A. 105, 7797-7802. doi:10.1073/pnas.0800928105
99. Setoguchi, R., Hori, S., Takahashi, T., and Sakaguchi, S. (2005). Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723-735. doi:10.1084/jem.20041982
100. Sgouroudis, E., Albanese, A., and Piccirillo, C. A. (2008). Impact of protective IL-2 allelic variants on CD4+ Foxp3+ regulatory T cell function in situ and resistance to autoimmune diabetes in NOD mice. J. Immunol. 181, 6283-6292.
101. Sgouroudis, E., Kornete, M., and Piccirillo, C. A. (2011). IL-2 production by dendritic cells promotes Foxp3(+) regulatory T-cell expansion in autoimmune-resistant NOD congenic mice. Autoimmunity 44, 406-414. doi:10.3109/08916934.2010.536795
102. Shin, H. J., Baker, J., Leveson-Gower, D. B., Smith, A. T., Sega, E. I., and Negrin, R. S., (2011). Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells. Blood 118:2342-2350. doi:10.1182/blood-2010-10-313684
103. Shull, M. M., Ormsby, I., Kier, A. B., Pawlowski, S., Diebold, R. J., Yin, M., et al. (1992). Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359, 693-699. doi:10.1038/359693a0
104. Smith, K. A., Baker, P. E., Gillis, S., and Ruscetti, F. W. (1980). Functional and molecular characteristics of T-cell growth factor. Mol. Immunol. 17, 579-589. doi:10.1016/0161-5890(80)90156-X
105. Soper, D. M., Kasprowicz, D. J., and Ziegler, S. F. (2007). IL-2Rbeta links IL-2R signaling with Foxp3 expression. Eur. J. Immunol. 37, 1817-1826. doi:10.1002/eji.200737101
106. Strainic, M. G., Shevach, E. M., An, F., Lin, F., and Medof, M. E. (2013). Absence of signaling into CD4(+) cells via C3aR and C5aR enables autoinductive TGF-beta1 signaling and induction of Foxp3(+) regulatory T cells. Nat. Immunol. 14, 162-171. doi:10.1038/ni.2499
107. Sugimoto, N., Oida, T., Hirota, K., Nakamura, K., Nomura, T., Uchiyama, T., et al. (2006). Foxp3-dependent and -independent molecules specific for CD25+CD4+ natural regulatory T cells revealed by DNA microarray analysis. Int. Immunol. 18, 1197-1209. doi:10.1093/intimm/dxl060
108. Sun, C. M., Hall, J. A., Blank, R. B., Bouladoux, N., Oukka, M., Mora, J. R., et al. (2007). Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775-1785. doi:10.1084/jem.20070602
109. Sun, S. C. (2011). Non-canonical NF-kappaB signaling pathway. Cell Res. 21, 71-85. doi:10.1038/cr.2010.177
110. Suzuki, H., Kundig, T. M., Furlonger, C., Wakeham, A., Timms, E., Matsuyama, T., et al. (1995). Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268, 1472-1476. doi:10.1126/science.7770771
111. Tang, Q., Adams, J. Y., Penaranda, C., Melli, K., Piaggio, E., Sgouroudis, E., et al. (2008). Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687-697. doi:10.1016/j.immuni.2008.03.016
112. Todd, J. A., Walker, N. M., Cooper, J. D., Smyth, D. J., Downes, K., Plagnol, V., et al. (2007). Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat. Genet. 39, 857-864. doi:10.1038/ng2068
113. Toker, A., Engelbert, D., Garg, G., Polansky, J. K., Floess, S., Miyao, T., et al. (2013). Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J. Immunol. 190, 3180-3188. doi:10.4049/jimmunol.1203473
114. Tone, Y., Furuuchi, K., Kojima, Y., Tykocinski, M. L., Greene, M. I., and Tone, M. (2008). Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194-202. doi:10.1038/ni1549
115. Valencia, X., Stephens, G., Goldbach-Mansky, R., Wilson, M., Shevach, E. M., and Lipsky, P. E. (2006). TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 108, 253-261. doi:10.1182/blood-2005-11-4567
116. van Mierlo, G. J., Scherer, H. U., Hameetman, M., Morgan, M. E., Flierman, R., Huizinga, T. W., et al. (2008). Cutting edge: TNFR-shedding by CD4+CD25+ regulatory T cells inhibits the induction of inflammatory mediators. J. Immunol. 180, 2747-2751.
117. Vella, A., Cooper, J. D., Lowe, C. E., Walker, N., Nutland, S., Widmer, B., et al. (2005). Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773-779. doi:10.1086/429843
118. Vignali, D. A., Collison, L. W., and Workman, C. J. (2008). How regulatory T cells work. Nat. Rev. Immunol. 8, 523-532. doi:10.1038/nri2343
119. Walker, M. R., Kasprowicz, D. J., Gersuk, V. H., Benard, A., Van Landeghen, M., Buckner, J. H., et al. (2003). Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25-T cells. J. Clin. Invest. 112, 1437-1443. doi:10.1172/JCI200319441
120. Wang, Y., Su, M. A., and Wan, Y. Y. (2011). An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35, 337-348. doi:10.1016/j.immuni.2011.08.012
121. Webster, K. E., Walters, S., Kohler, R. E., Mrkvan, T., Boyman, O., Surh, C. D., et al. (2009). In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J. Exp. Med. 206, 751-760. doi:10.1084/jem.20082824
122. Willenborg, D. O., Fordham, S. A., Cowden, W. B., and Ramshaw, I. A. (1995). Cytokines and murine autoimmune encephalomyelitis: inhibition or enhancement of disease with antibodies to select cytokines, or by delivery of exogenous cytokines using a recombinant vaccinia virus system. Scand. J. Immunol. 41, 31-41. doi:10.1111/j.1365-3083.1995.tb03530.x
123. Willerford, D. M., Chen, J., Ferry, J. A., Davidson, L., Ma, A., and Alt, F. W. (1995). Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521-530. doi:10.1016/1074-7613(95)90180-9
124. Wilson, M. S., Pesce, J. T., Ramalingam, T. R., Thompson, R. W., Cheever, A., and Wynn, T. A. (2008). Suppression of murine allergic airway disease by IL-2:anti-IL-2 monoclonal antibody-induced regulatory T cells. J. Immunol. 181, 6942-6954.
125. Wohlfert, E. A., Grainger, J. R., Bouladoux, N., Konkel, J. E., Oldenhove, G., Ribeiro, C. H., et al. (2011). GATA3 controls Foxp3(+) regulatory T cell fate during inflammation in mice. J. Clin. Invest. 121, 4503-4515. doi:10.1172/JCI57456
126. Wu, A. J., Hua, H., Munson, S. H., and McDevitt, H. O. (2002). Tumor necrosis factor-alpha regulation of CD4+CD25+ T cell levels in NOD mice. Proc. Natl. Acad. Sci. U.S.A. 99, 12287-12292. doi:10.1073/pnas.172382999
127. Wu, Y., Borde, M., Heissmeyer, V., Feuerer, M., Lapan, A. D., Stroud, J. C., et al. (2006). FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375-387. doi:10.1016/j.cell.2006.05.042
128. Xu, L., Kitani, A., and Strober, W. (2010). Molecular mechanisms regulating TGF-beta-induced Foxp3 expression. Mucosal Immunol. 3, 230-238. doi:10.1038/mi.2010.7
129. Yamanouchi, J., Rainbow, D., Serra, P., Howlett, S., Hunter, K., Garner, V. E., et al. (2007). Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39, 329-337. doi:10.1038/ng1958
130. Yamazaki, S., Bonito, A. J., Spisek, R., Dhodapkar, M., Inaba, K., and Steinman, R. M. (2007). Dendritic cells are specialized accessory cells along with TGF-for the differentiation of Foxp3+ CD4+ regulatory T cells from peripheral Foxp3 precursors. Blood 110, 4293-4302. doi:10.1182/blood-2007-05-088831
131. Yamazaki, S., Dudziak, D., Heidkamp, G. F., Fiorese, C., Bonito, A. J., Inaba, K., et al. (2008). CD8+ CD205+ splenic dendritic cells are specialized to induce Foxp3+ regulatory T cells. J. Immunol. 181, 6923-6933.
132. Yang, X. D., Tisch, R., Singer, S. M., Cao, Z. A., Liblau, R. S., Schreiber, R. D., et al. (1994). Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J. Exp. Med. 180, 995-1004. doi:10.1084/jem.180.3.995
133. 5a/b in directly regulating Foxp3. Blood 109, 4368-4375. doi:10.1182/blood-2006-11-055756
134. Zanin-Zhorov, A., Ding, Y., Kumari, S., Attur, M., Hippen, K. L., Brown, M., et al. (2010). Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 328, 372-376. doi:10.1126/science.1186068
135. Zhang, N., and Bevan, M. J. (2012). TGF-beta signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat. Immunol. 13, 667-673. doi:10.1038/ni.2319
136. Zhang, Q., Cui, F., Fang, L., Hong, J., Zheng, B., and Zhang, J. Z. (2013). TNF-alpha impairs differentiation and function of TGF-beta-induced Treg cells in autoimmune diseases through Akt and Smad3 signaling pathway. J. Mol. Cell Biol. 5, 85-98. doi:10.1093/jmcb/mjs063
137. Zheng, S. G., Wang, J., Wang, P., Gray, J. D., and Horwitz, D. A. (2007). IL-2 is essential for TGF-beta to convert naive CD4+CD25-cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J. Immunol. 178, 2018-2027.
138. Zheng, Y., Josefowicz, S., Chaudhry, A., Peng, X. P., Forbush, K., and Rudensky, A. Y. (2010). Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808-812. doi:10.1038/nature08750
139. Zhou, X., Bailey-Bucktrout, S. L., Jeker, L. T., Penaranda, C., Martinez-Llordella, M., Ashby, M., et al. (2009). Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000-1007. doi:10.1038/ni.1774
140. 25+ regulatory T cells through a STAT-dependent mechanism and induces the expansion of these cells in vivo. Blood 108, 1571-1579. doi:10.1182/blood-2006-02-004747