Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1

Nature Communications

Volumn 6, Issue , 2015, Pages

  Bothur, Evita ^a   Raifer, Hartmann ^a   Haftmann, Claudia ^b   Stittrich, Anna Barbara ^b   Brustle, Anne ^c   Brenner, Dirk ^c,d,e   Bollig, Nadine ^a   Bieringer, Maria ^a   Kang, Chol Ho ^a   Reinhard, Katharina ^a   Camara, Barbel ^a   Huber, Magdalena ^a   Visekruna, Alexander ^a   Steinhoff, Ulrich ^a   Repenning, Antje ^a   Bauer, Uta Maria ^a   Sexl, Veronika ^f   Radbruch, Andreas ^b   Sparwasser, Tim ^g   Mashreghi, Mir Farzin ^b   Wah Mak, Tak ^c   Lohoff, Michael ^a   more..

^a PHILIPPS UNIVERSITY MARBURG   (Germany)

^b CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^c Australian National University   (Australia)

^d LUXEMBOURG INSTITUTE OF HEALTH   (Luxembourg)

^e UNIVERSITY OF SOUTHERN DENMARK   (Denmark)

^f UNIVERSITY OF VETERINARY MEDICINE   (Austria)

^g INSTITUTE OF INFECTION IMMUNOLOGY   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CALCINEURIN; CD28 ANTIGEN; CD3 ANTIGEN; CD4 ANTIGEN; DUAL SPECIFICITY PHOSPHATASE 3; INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR BETA; INTERLEUKIN 6; MAMMALIAN TARGET OF RAPAMYCIN; MESSENGER RNA; MICRORNA 182; MITOGEN ACTIVATED PROTEIN KINASE; NON RECEPTOR PROTEIN TYROSINE PHOSPHATASE 2; PROTEIN KINASE B; PROTEIN TYROSINE PHOSPHATASE 1B; PROTEIN TYROSINE PHOSPHATASE SHP 1; SMAD3 PROTEIN; STAT5 PROTEIN; TRANSCRIPTION FACTOR FKHR; TRANSCRIPTION FACTOR FOXP3; TRANSCRIPTION FACTOR NFAT; TRANSFORMING GROWTH FACTOR BETA; FORKHEAD TRANSCRIPTION FACTOR; FOXO1 PROTEIN, MOUSE; FOXP3 PROTEIN, MOUSE; LYMPHOCYTE ANTIGEN RECEPTOR; PTPN2 PROTEIN, MOUSE;

ANTIGEN; BLOOD; GENE EXPRESSION; GENETIC ANALYSIS; IMMUNITY; PATHOGEN; PROTEIN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANTIGEN PRESENTING CELL; ANTIGEN RECOGNITION; ARTICLE; CELL EXPANSION; CONTROLLED STUDY; DOWN REGULATION; GENE SILENCING; GENETIC TRANSCRIPTION; IN VITRO STUDY; IN VIVO STUDY; INTRACELLULAR SIGNALING; LYMPHOCYTE PROLIFERATION; MAJOR HISTOCOMPATIBILITY COMPLEX; MOUSE; NONHUMAN; PROTEIN DEPLETION; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REGULATORY T LYMPHOCYTE; UPREGULATION; WESTERN BLOTTING; ANIMAL; CD4+ T LYMPHOCYTE; CELL CULTURE; FEMALE; FLOW CYTOMETRY; GENETICS; MALE; METABOLISM;

ANIMALS; BLOTTING, WESTERN; CD4-POSITIVE T-LYMPHOCYTES; CELLS, CULTURED; FEMALE; FLOW CYTOMETRY; FORKHEAD BOX PROTEIN O1; FORKHEAD TRANSCRIPTION FACTORS; MALE; MICE; PROTEIN TYROSINE PHOSPHATASE, NON-RECEPTOR TYPE 2; RECEPTORS, ANTIGEN, T-CELL; T-LYMPHOCYTES, REGULATORY;

EID: 84944144932     PISSN: None     EISSN: 20411723     Source Type: Journal    
DOI: 10.1038/ncomms9576     Document Type: Article

References (58)

1. Sakaguchi, S., Yamaguchi, T., Nomura, T., Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775-787 (2008).
2. Shevach, E. M. Biological functions of regulatory T cells. Adv. Immunol. 112, 137-176 (2011).
3. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395-399 (2012).
4. Shevach, E. M., Thornton, A. M. tTregs, pTregs, and iTregs: similarities and differences. Immunol. Rev. 259, 88-102 (2014).
5. 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. 198, 1875-1886 (2003).
6. Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18-20 (2001).
7. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20-21 (2001).
8. Fontenot, J. D., Gavin, M. A., Rudensky, A. Y. Foxp3 programs the development and function of CD4\+CD25\+ regulatory T cells. Nat. Immunol. 4, 330-336 (2003).
9. Hill, J. A. et al. Foxp3 transcription-factor-dependent and-independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786-800 (2007).
10. Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931-935 (2007).
11. 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).
12. Visekruna, A. et al. c-Rel is crucial for the induction of Foxp3(\+) regulatory CD4(\+) T cells but not T(H)17 cells. Eur. J. Immunol. 40, 671-676 (2010).
13. Long, M., Park, S. G., Strickland, I., Hayden, M. S., Ghosh, S. Nuclear factorkappaB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921-931 (2009).
14. Ruan, Q. et al. Development of Foxp3(\+) regulatory t cells is driven by the c-Rel enhanceosome. Immunity 31, 932-940 (2009).
15. Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).
16. 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).
17. Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194-202 (2008).
18. Burchill, M. A., Yang, J., Vogtenhuber, C., Blazar, B. R., Farrar, M. A. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3\+ regulatory T cells. J. Immunol. 178, 280-290 (2007).
19. 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).
20. Harada, Y. et al. 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. 207, 1381-1391 (2010).
21. Ouyang, W. et al. Foxo proteins cooperatively control the differentiation of Foxp3\+ regulatory T cells. Nat. Immunol. 11, 618-627 (2010).
22. Kerdiles, Y. M. et al. Foxo transcription factors control regulatory T cell development and function. Immunity 33, 890-904 (2010).
23. Brunet, A. et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96, 857-868 (1999).
24. Haxhinasto, S., Mathis, D., Benoist, C. The AKT-mTOR axis regulates de novo differentiation of CD4\+Foxp3\+ cells. J. Exp. Med. 205, 565-574 (2008).
25. Sauer, S. et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl Acad. Sci. USA 105, 7797-7802 (2008).
26. Merkenschlager, M., von Boehmer, H. PI3 kinase signalling blocks Foxp3 expression by sequestering Foxo factors. J. Exp. Med. 207, 1347-1350 (2010).
27. Gomez-Rodriguez, J. et al. Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells. J. Exp. Med. 211, 529-543 (2014).
28. Gabrysova, L. et al. Integrated T-cell receptor and costimulatory signals determine TGF-beta-dependent differentiation and maintenance of Foxp3\+ regulatory T cells. Eur. J. Immunol. 41, 1242-1248 (2011).
29. Ma, J., Ding, Y., Fang, X., Wang, R., Sun, Z. Protein kinase C-theta inhibits inducible regulatory T cell differentiation via an AKT-Foxo1/3a-dependent pathway. J. Immunol. 188, 5337-5347 (2012).
30. Zanin-Zhorov, A. et al. Protein kinase C-theta mediates negative feedback on regulatory T cell function. Science 328, 372-376 (2010).
31. Chang, X. et al. The kinases MEKK2 and MEKK3 regulate transforming growth factor-beta-mediated helper T cell differentiation. Immunity 34, 201-212 (2011).
32. 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. 186, 6329-6337 (2011).
33. Komatsu, N. et al. Pathogenic conversion of Foxp3\+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62-68 (2014).
34. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat. Immunol. 10, 1000-1007 (2009).
35. Rubtsov, Y. P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667-1671 (2010).
36. Selvaraj, R. K., Geiger, T. L. A kinetic and dynamic analysis of Foxp3 induced in T cells by TGF-beta. J. Immunol. 178, 7667-7677 (2007).
37. Lahl, K. et al. Selective depletion of Foxp3\+ regulatory T cells induces a scurfylike disease. J. Exp. Med. 204, 57-63 (2007).
38. Lee, I. H., Li, W. P., Hisert, K. B., Ivashkiv, L. B. Inhibition of interleukin 2 signaling and signal transducer and activator of transcription (STAT)5 activation during T cell receptor-mediated feedback inhibition of T cell expansion. J. Exp. Med. 190, 1263-1274 (1999).
39. Li, L. et al. A critical role for SHP2 in STAT5 activation and growth factormediated proliferation, survival, and differentiation of human CD34\+ cells. Blood 118, 1504-1515 (2011).
40. Aoki, N., Matsuda, T. A nuclear protein tyrosine phosphatase TC-PTP is a potential negative regulator of the PRL-mediated signaling pathway: dephosphorylation and deactivation of signal transducer and activator of transcription 5a and 5b by TC-PTP in nucleus. Mol. Endocrinol. 16, 58-69 (2002).
41. Gu, F. et al. Protein tyrosine phosphatase 1B attenuates growth hormonemediated JAK2-STAT signaling. Mol. Cell. Biol. 23, 3753-3762 (2003).
42. Irie-Sasaki, J. et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signalling. Nature 409, 349-354 (2001).
43. Stittrich, A. B. et al. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat. Immunol. 11, 1057-1062 (2010).
44. Essaghir, A., Dif, N., Marbehant, C. Y., Coffer, P. J., Demoulin, J. B. The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors. J. Biol. Chem. 284, 10334-10342 (2009).
45. Yamazaki, S. et al. TGF-beta as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood 113, 1250-1256 (2009).
46. Asada, S. et al. Mitogen-activated protein kinases, Erk and p38, phosphorylate and regulate Foxo1. Cell. Signal. 19, 519-527 (2007).
47. You-Ten, K. E. et al. Impaired bone marrow microenvironment and immune function in T cell protein tyrosine phosphatase-deficient mice. J. Exp. Med. 186, 683-693 (1997).
48. Wiede, F. et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J. Clin. Invest. 121, 4758-4774 (2011).
49. Wiede, F., La Gruta, N. L., Tiganis, T. PTPN2 attenuates T-cell lymphopeniainduced proliferation. Nat. Commun. 5, 3073 (2014).
50. Spalinger, M. R. et al. PTPN2 controls differentiation of CD4(\+) T cells and limits intestinal inflammation and intestinal dysbiosis. Mucosal Immunol. 8, 918-929 (2015).
51. Long, S. A. et al. An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2 R signaling in CD4(\+) T cells. Genes Immun. 12, 116-125 (2011).
52. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256-260 (2007).
53. Wan, Y. Y., Flavell, R. A. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc. Natl Acad. Sci. USA 102, 5126-5131 (2005).
54. Barnden, M. J., Allison, J., Heath, W. R., Carbone, F. R. Defective TCR expression in transgenic mice constructed using cDNA-based alpha-and betachain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34-40 (1998).
55. Lohoff, M. et al. Deficiency in the transcription factor interferon regulatory factor (IRF)-2 leads to severely compromised development of natural killer and T helper type 1 cells. J. Exp. Med. 192, 325-336 (2000).
56. Brustle, A. et al. The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat. Immunol. 8, 958-966 (2007).
57. Raifer, H. et al. Unlike alphabeta T cells, gammadelta T cells, LTi cells and NKT cells do not require IRF4 for the production of IL-17A and IL-22. Eur. J. Immunol. 42, 3189-3201 (2012).
58. Zhu, J., Cote-Sierra, J., Guo, L., Paul, W. E. Stat5 activation plays a critical role in Th2 differentiation. Immunity 19, 739-748 (2003).