FOXP3 and scurfy: How it all began

Nature Reviews Immunology

Volumn 14, Issue 5, 2014, Pages 343-349

  Ramsdell, Fred ^a   Ziegler, Steven F ^b  

^a NOVO NORDISK INC   (United States)

^b BENAROYA RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; TRANSCRIPTION FACTOR FOXP3;

ANTIGEN EXPRESSION; AUTOIMMUNITY; CD4+ T LYMPHOCYTE; GENE MUTATION; HUMAN; LYMPHOCYTE ACTIVATION; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN FUNCTION; REGULATORY MECHANISM; REGULATORY T LYMPHOCYTE; REVIEW; SUPPRESSOR CELL;

ANIMALS; FORKHEAD TRANSCRIPTION FACTORS; HUMANS; IMMUNE SYSTEM; T-LYMPHOCYTES, REGULATORY;

EID: 84899659467     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri3650     Document Type: Review

References (82)

1. Russell, W. L. X.ray induced mutations in mice. Cold Spring Harb. Symp. Quant. Biol. 16, 327-336 (1951).
2. Russell, W. L., Russell, L. B. & Kelly, E. M. Radiation dose rate and mutation frequency. Science 128, 1546-1550 (1958).
3. Russell, W. L., Russell, L. B. & Gower, J. S. Exceptional inheritance of a sex-linked gene in the mouse explained on the basis that the X/O sexchromosome constitution is female. Proc. Natl Acad. Sci. USA 45, 554-560 (1959).
4. Godfrey, V., Wilkinson, J. E., Rinchik, E. M. & Russell, L. B. Fatal lymphoreticular disease in the scurfy (sf) mouse requires T cells that mature in a sf thymic environment: Potential model for thymic education. Proc. Natl Acad. Sci, USA 88, 5528-5532 (1991).
5. Godfrey, V., Wilkinson, J. E. & X.linked lymphoreticular disease in the scrufy (sf) mutant mouse. Am. J. Pathol. 138, 1379-1387 (1991).
6. Godfrey, V., Rouse, B. T. & Wilkinson, J. E. Transplantation of T cell-mediated lymphoreticular disease from the scurfy (sf) mouse. Am. J. Pathol. 145, 281-286 (1994).
7. Kanangat, S. et al. Disease in the scurfy (sf) mouse is associated with overexpression of cytokine genes. Eur. J. Immunol. 26, 161-165 (1996).
8. Zahorsky-Reeves, J. L. & Wilkinson, J. E. The murine mutations scurfy (sf) results in an antigen-dependent lymphoproliferative disease with altered T cell sensitivity. Eur. J. Immunol. 31, 196-204 (2001).
9. Blair, P. J. et al. CD4+CD8. T cells are the effector cells in disease pathogenesis in the scurfy (sf) mouse. J. Immunol. 153, 3764-3774 (1994).
10. Tivol, E. A. et al. Loss of CTLA.4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA.4. Immunity 3, 541-547 (1995).
11. Waterhouse, P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla.4. Science 270, 985-988 (1995).
12. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nature Genet. 27, 68-73 (2001).
13. Khattri, R. et al. The amount of scurfin protein determines peripheral T cell number and responsiveness. J. Immunol. 167, 6312-6320 (2001).
14. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL.2 receptor f-chains (CD25). Breakdown of a single mechanism of selftolerance causes various autoimmune diseases. J. Immunol. 155, 1151-1164 (1995).
15. Shevach, E. M. Regulatory T cells in autoimmunity. Annu. Rev. Immunol. 18, 423-449 (2000).
16. Thornton, A. M. & Shevach, E. M. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J. Exp. Med. 188, 287-296 (1998).
17. Takahashi, T. et al. Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int. Immunol. 10, 1969-1980 (1998).
18. Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol. 4, 337-342 (2003).
19. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057-1061 (2003).
20. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. FoxP3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330-336 (2003).
21. Powell, B. R., Buist, N. & Stenzel, P. An X.linked syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. J. Pediatr. 100, 731-737 (1982).
22. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X.linked syndrome (IPEX) is caused by mutation of FOXP3. Nature Genet. 27, 20-21 (2001).
23. Wildin, R. S. et al. X.linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nature Genet. 27, 18-20 (2001).
24. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329-341 (2005).
25. Lahl, K. et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57-63 (2007).
26. Kim, J. M., Rasmussen, J. P. & Rudensky, A. Y. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nature Immunol. 8, 191-197 (2007).
27. Bluestone, J. A. & Abbas, A. K. Natural versus adapted regulatory T cells. Nature Rev. Immunol. 3, 253-257 (2003).
28. Yadav, M., Stephan, S. & Bluestone, J. A. Peripherally induced Tregs - role in immune homeostasis and autoimmunity. Front. Immunol. 4, 232 (2013).
29. Lathrop, S. K., Santacruz, N. A., Pham, D., Luo, J. & Hsieh, C. S. Antigen-specific peripheral shaping of the natural regulatory T cell population. J. Exp. Med. 205, 3105-3117 (2008).
30. Kuczma, M. et al. TCR repertoire and Foxp3 expression define functionally distinct subsets of CD4+ regulatory T cells. J. Immunol. 183, 3118-3129 (2009).
31. Rubtsov, Y. P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667-1671 (2010).
32. 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 36, 262-275 (2012).
33. Sakaguchi, S., Vignali, D. A., Rudensky, A. Y., Niec, R. E. & Waldmann, H. The plasticity and stability of regulatory T cells. Nature Rev. Immunol. 13, 461-467 (2013).
34. Schubert, L. A., Jeffery, E. W., Zhang, Y., Ramsdell, F. & Ziegler, S. F. Scurfin (FOXP3) acts as a repressor of transcription and regulates T cell activation. J. Biol. Chem. 276, 37672-37679 (2001).
35. Lopes, J. E. et al. Analysis of FOXP3 reveals multiple domains required for its function as a transcriptional repressor. J. Immunol. 177, 3133-3142 (2006).
36. Li, B. et al. FOXP3 is a homo-oligomer and a component of a supramolecular regulatory complex disabled in the human XLAAD/IPEX auoimmune disease. Int. Immunol. 19, 825-835 (2007).
37. Li, B. et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl Acad. Sci. USA 104, 4571-4576 (2007).
38. Pan, F. et al. Eos mediates Foxp3.dependent gene silencing in CD4+ regulatory T cells. Science 325, 1142-1146 (2009).
39. Du, J., Huang, C., Zhou, B. & Ziegler, S. F. Isoformspecific inhibition of RORf-mediated transcriptional activation by human FOXP3. J. Immunol. 180, 4785-4792 (2008).
40. Zhou, L. et al. TGF-fÀ-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORfÁt function. Nature 453, 236-240 (2008).
41. Walker, M. R. et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25. T cells. J. Clin. Invest. 112, 1437-1443 (2003).
42. Bandukwala, H. S. et al. Structure of a domainswapped FOXP3 dimer on DNA and its function in regulatory T cells. Immunity 34, 479-491 (2011).
43. Ono, M. et al. Foxp3 controls regulatory T.cell function by interacting with AML1/Runx1. Nature 446, 685-689 (2007).
44. Bettelli, E., Dastrange, M. & Oukka, M. Foxp3 interacts with nuclear factor of activated T cells and NF.fÈB to repress cytokine gene expression and effector functions of T helper cells. Proc. Natl Acad. Sci. USA 102, 5138-5143 (2005).
45. Wu, Y. et al. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 126, 375-387 (2006).
46. Rudra, D. et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nature Immunol. 13, 1010-1019 (2012).
47. Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T.cell stimulation. Nature 445, 931-935 (2007).
48. Zheng, Y. et al. Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature 445, 936-940 (2007).
49. Mantel, P. Y. et al. Molecular mechanisms underlying FOXP3 induction in human T cells. J. Immunol. 176, 3593-3602 (2006).
50. Zorn, E. 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 108, 1571-1579 (2006).
51. Kim, H. P. & Leonard, W. J. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J. Exp. Med. 204, 1543-1551 (2007).
52. Baron, U. et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3+ conventional T cells. Eur. J. Immunol. 37, 2378-2389 (2007).
53. Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).
54. Huehn, J., Polansky, J. K. & Hamann, A. Epigenetic control of FOXP3 expression: the key to a stable regulatory T.cell lineage? Nature Rev. Immunol. 9, 83-89 (2009).
55. Polansky, J. K. et al. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38, 1654-1663 (2008).
56. Ruan, Q. et al. Development of Foxp3+ regulatory T cells is driven by the c.Rel enhanceosome. Immunity 31, 932-940 (2009).
57. Long, M., Park, S..G., Strickland, I., Hayden, M. S. & Ghosh, S. Nuclear factor-fÈB modeulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921-931 (2009).
58. Deenick, E. K. et al. c.Rel but not NF.fÈB1 is important for T regulatory cell development. Eur. J. Immunol. 40, 677-681 (2010).
59. Visekruna, A. et al. c.Rel is crucial for the induction of Foxp3+ regulatory CD4+ T cells but not TH17 cells. Eur. J. Immunol. 40, 671-676 (2010).
60. Isomura, I. et al. c.Rel is required for the development of thymic Foxp3+ CD4 regulatory T cells. J. Exp. Med. 206, 3001-3014 (2009).
61. Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T?cell fate. Nature 463, 808-812 (2010).
62. Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through it enhancer. Nature Immunol. 9, 194-202 (2008).
63. Kitoh, A. et al. Indispensable role of gthe Runx1?Cbfβ transcription complex for in vivo-suppressive function of FoxP3+ regulatory T cells. Immunity 31, 609-620 (2009).
64. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395-399 (2012).
65. 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 150, 29-38 (2012).
66. Walker, M. R., Carson, B. D., Nepom, G. T., Ziegler, S. F. & Buckner, J. H. De novo generation of antigen-specific CD4+CD25+ regulatory T cells from human CD4+CD25- cells. Proc. Natl Acad. Sci. USA 102, 4103-4108 (2005).
67. Gavin, M. A. 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 103, 6659-6664 (2006).
68. Allan, S. E. et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int. Immunol. 19, 345-354 (2007).
69. Allan, S. E. et al. The role of 2 FOXP3 isoforms in the generation of human CD4+ Tregs. J. Clin. Invest. 115, 3276-3284 (2005).
70. Smith, E. L., Finney, H. M., Nesbitt, A. M., Ramsdell, F. & Robinson, M. K. Splice variants of human FOXP3 are functional inhibitors of human CD4+ T?cell activation. Immunology 119, 203-211 (2006).
71. Huang, C. et al. Cutting Edge: a novel, human-specific interacting protein couples FOXP3 to a chromatin-remodeling complex that contains KAP1/TRIM28. J. Immunol. 190, 4470-4473 (2013).
72. Chatila, T. A. et al. JM2, encoding a fork head-related protein, is mutated in X?linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106, R75-R81 (2000).
73. Chen, W. et al. Conversion of peripheral CD4+CD25- T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor FoxP3. J. Exp. Med. 198, 1875-1886 (2003).
74. Bacchetta, R. et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J. Clin. Invest. 116, 1713-1722 (2006).
75. Hill, J. A. et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786-800 (2007).
76. Gavin, M. A. et al. Foxp3?dependent programme of regulatory T?cell differentiation. Nature 445, 771-775 (2007).
77. Lin, W. et al. Regulatory T cell development in the absence of functional Foxp3. Nature Immunol. 8, 359-368 (2007).
78. Williams, L. M. & Rudensky, A. Y. Maintenance of the Foxp3?dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nature Immunol. 8, 277-284 (2007).
79. Burchill, M. A., Yang, J., Vogtenhuber, C., Blazar, B. R. & Farrar, M. A. IL?2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178, 280-290 (2007).
80. Zhang, F., Meng, G. & Strober, W. Interactions among the transcription factors Runx1, RORγt and Foxp3 regulate the differentiation of interleukin 17?producing T cells. Nature Immunol. 9, 1297-1306 (2008).
81. Rudra, D. et al. Runx-CBFβ complexes control expression of the transcription factor Foxp3 in regulatory T cells. Nature Immunol. 10, 1170-1177 (2009).
82. Samstein, R. M. et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151, 153-166 (2012).