Research progress of antigen-specific regulatory T cells for clinical application_West China Medical Journal

Authors：

JIN Xi ,  LI Hong

Institute of Urology, Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LI Hong, Email: wzwzlwww@qq.com

Keywords：

Regulatory T cells; Antigen specificity; Expansion; Therapy

DOI：

10.7507/1002-0179.201707024

Video：

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Abstract Full text Figures/Tables Video References Cited by

Regulatory T cells (Treg) are critical for regulation of tolerance, control immune responses to self-antigens thereby preventing autoimmunity, and limiting responses to foreign antigens thereby minimizing T cell-mediated immunopathology. Recent data indicate that suppression of organ-specific autoimmunity is dependent on the antigen specificity of Treg. An emerging model of Treg action is that organ-specific Treg acquire suppressive activity through activation by dendritic cells expressing specific antigens. Thus, the efficacy of Treg-based therapy should be increased by using antigen-specific Treg rather than polyclonal Treg. It is necessary to identify relevant antigens and to expand antigen-specific Treg from polyclonal populations. Here, we discuss recent techniques for expansion of antigen-specific Treg, function and antigen specificity of Treg and the therapeutic potential of Treg in controlling autoimmune disease and inducing transplant tolerance.

Citation： JIN Xi, LI Hong. Research progress of antigen-specific regulatory T cells for clinical application. West China Medical Journal, 2018, 33(5): 616-622. doi: 10.7507/1002-0179.201707024 Copy

1.	Sakaguchi S. Naturally arising Foxp3-expressing CD25⁺CD4⁺ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol, 2005, 6(4): 345-352.
2.	Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance. Cell, 2008, 133(5): 775-787.
3.	Tadokoro CE, Shakhar G, Shen SQ, et al. Regulatory T cells inhibit stable contacts between CD4(+) T cells and dendritic cells in vivo. J Exp Med, 2006, 203(3): 505-511.
4.	Li CR, Baaten BJ, Bradley LM. Harnessing memory adaptive regulatory T cells to control autoimmunity in type 1 diabetes. J Mol Cell Biol, 2012, 4(1): 38-47.
5.	Duran-Struuck R, Sondermeijer HP, Bühler L, et al. Effect of ex vivo-expanded recipient regulatory T cells on hematopoietic chimerism and kidney allograft tolerance across MHC barriers in cynomolgus macaques. Transplantation, 2017, 101(2): 274-283.
6.	Heinrichs J, Bastian D, Veerapathran A, et al. Regulatory T-Cell therapy for graft-versus-host disease. J Immunol Res Ther, 2016, 1(1): 1-14.
7.	Bluestone JA, Buckner JH, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med, 2015, 7(315): 315ra189.
8.	Hsieh CS, Liang Y, Tyznik AJ, et al. Recognition of the peripheral self by naturally arising CD25⁺ CD4⁺ T cell receptors. Immunity, 2004, 21(2): 267-277.
9.	Sagoo P, Lombardi G, Lechler RI. Relevance of regulatory T cell promotion of donor-specific tolerance in solid organ transplantation. Front Immunol, 2012, 3(3): 184.
10.	Tsaur I, Gasser M, Aviles B, et al. Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients. Kidney Int, 2011, 79(9): 1005-1012.
11.	Hoffmann P, Eder R, Edinger M. Polyclonal expansion of human CD4(+)CD25(+) regulatory T cells. Methods Mol Biol, 2011, 677: 15-30.
12.	Pilat N, Klaus C, Gattringer M, et al. Therapeutic efficacy of polyclonal tregs does not require rapamycin in a low-dose irradiation bone marrow transplantation model. Transplantation, 2011, 92(3): 280-288.
13.	Zwar TD, Read S, van Driel IR, et al. CD4⁺CD25⁺ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo. J Immunol, 2006, 176(3): 1609-1617.
14.	Cheraï M, Hamel Y, Baillou C, et al. Generation of human alloantigen-specific regulatory T cells under good manufacturing practice-compliant conditions for cell therapy. Cell Transplant, 2015, 24(12): 2527-2540.
15.	Hoffmann P, Eder R, Edinger M. Polyclonal expansion of human CD4(+)CD25(+) regulatory T cells. Methods Mol Biol, 2011, 677: 15-30.
16.	He X, Smeets RL, van Rijssen E, et al. Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells. Sci Rep, 2017, 7(7): 43003.
17.	Thornton AM, Shevach EM. CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med, 1998, 188(2): 287-296.
18.	Jin X, Wang Y, Hawthorne WJ, et al. Enhanced suppression of the xenogeneic T-cell response in vitro by xenoantigen stimulated and expanded regulatory T cells. Transplantation, 2014, 97(1): 30-38.
19.	Jeffery HC, Jeffery LE, Lutz P, et al. Low-dose interleukin-2 promotes STAT-5 phosphorylation, Treg survival and CTLA-4-dependent function in autoimmune liver diseases. Clin Exp Immunol, 2017, 188(3): 394-411.
20.	Peters JH, Hilbrands LB, Koenen HJ, et al. Ex vivo Generation of human alloantigen-specific regulatory T cells from CD4(pos)CD25(high) T cells for immunotherapy. PLoS One, 2008, 3(5): e2233.
21.	Jiang S, Tsang J, Game DS, et al. Generation and expansion of human CD4⁺ CD25⁺ regulatory T cells with indirect allospecificity: Potential reagents to promote donor-specific transplantation tolerance. Transplantation, 2006, 82(12): 1738-1743.
22.	Wiesinger M, Stoica D, Roessner S et al. Good manufacturing practice-compliant production and lot-release of ex vivo expanded regulatory T cells as basis for treatment of patients with autoimmune and inflammatory disorders. Front Immunol, 2017, 8: 1371.
23.	Novak EJ, Masewicz SA, Liu AW, et al. Activated human epitope-specific T cells identified by class Ⅱ tetramers reside within a CD4^high, proliferating subset. Int Immunol, 2001, 13(6): 799-806.
24.	Jin X, Lu Y, Zhao Y, et al. Large-scale in vitro expansion of human regulatory T cells with potent xenoantigen-specific suppression. Cytotechnology, 2016, 68(4): 935-945.
25.	Yamazaki S, Patel M, Harper A, et al. Effective expansion of alloantigen-specific Foxp3⁺ CD25⁺ CD4⁺ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc Natl Acad Sci USA, 2006, 103(8): 2758-2763.
26.	Litjens NH, Boer K, Zuijderwijk JM, et al. Allogeneic mature human dendritic cells generate superior alloreactive regulatory T cells in the presence of IL-15. J Immunol, 2015, 194(11): 5282-5293.
27.	Fisson S, Djelti F, Trenado A, et al. Therapeutic potential of self-antigen-specific CD4⁺ CD25⁺ regulatory T cells selected in vitro from a polyclonal repertoire. Eur J Immunol, 2006, 36(4): 817-827.
28.	Chen WJ, Jin WW, Hardegen N, 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(12): 1875-1886.
29.	Fantini MC, Becker C, Monteleone G, et al. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol, 2004, 172(9): 5149-5153.
30.	Long SA, Walker MR, Rieck M, et al. Functional islet-specific Treg can be generated from CD4+CD25- T cells of healthy and type 1 diabetic subjects. Eur J Immunol, 2009, 39(2): 612-620.
31.	Tu W, Lau YL, Zheng J, et al. Efficient Generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells. Blood, 2008, 112(6): 2554-2562.
32.	Zheng J, Liu Y, Qin G, et al. Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells. J Immunol, 2009, 183(6): 3742-3750.
33.	Fourcade J, Sun Z, Kudela P, et al. Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire. J Immunol, 2010, 184(12): 6709-6718.
34.	Wu J, Hu M, Qian YW, et al. In vivo costimulation-blockade induced regulatory T cells demonstrate dominant and specific tolerance to porcine islet-xenografts. Transplantation, 2017, 101(7): 1587-1599.
35.	Jordan MS, Boesteanu A, Reed AJ, et al. Thymic selection of CD4⁺CD25⁺ regulatory T cells induced by an agonist self-peptide. Nat Immunol, 2001, 2(4): 301-306.
36.	Kronenberg M, Rudensky A. Regulation of immunity by self-reactive T cells. Nature, 2005, 435(742): 598-604.
37.	Spence A, Tang QZ. Restoring regulatory T cells in type 1 diabetes. Curr Diab Rep, 2016, 16(11): 110.
38.	Karim M, Feng G, Wood KJ, et al. CD25⁺CD4⁺ regulatory T cells generated by exposure to a model protein antigen prevent allograft rejection: antigen-specific reactivation in vivo is critical for bystander regulation. Blood, 2005, 105(12): 4871-4877.
39.	Yi S, Ji M, Wu J, et al. Adoptive transfer with in vitro expanded human regulatory T cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice. Diabetes, 2012, 61(5): 1180-1191.
40.	Tang Q, Adams JY, Tooley AJ, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol, 2006, 7(1): 83-92.
41.	Miller MJ, Safrina O, Parker I, et al. Imaging the single cell dynamics of CD4⁺ T cell activation by dendritic cells in lymph nodes. J Exp Med, 2004, 200(7): 847-856.
42.	Stoll S, Delon J, Brotz TM, et al. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science, 2002, 296(5574): 1873-1876.
43.	Germain RN, Miller MJ, Dustin ML, et al. Dynamic imaging of the immune system: progress, pitfalls and promise. Nat Rev Immunol, 2006, 6(7): 497-507.
44.	Kukreja A, Cost G, Marker J, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest, 2002, 109(1): 131-140.
45.	Perri V, Russo B, Crinò A, et al. Expression of PD-1 molecule on regulatory T lymphocytes in patients with insulin-dependent diabetes mellitus. Int J Mol Sci, 2015, 16(9): 22584-22605.
46.	Tang QZ, Henriksen KJ, Bi MY, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med, 2004, 199(11): 1455-1465.
47.	Masteller EL, Warner MR, Tang Q, et al. Expansion of functional endogenous antigen-specific CD4⁺CD25⁺ regulatory T cells from nonobese diabetic mice. J Immunol, 2005, 175(5):3053-3059.
48.	Tran GT, Hodgkinson SJ, Carter NM, et al. IL-5 promotes induction of antigen-specific CD4⁺CD25⁺ T regulatory cells that suppress autoimmunity. Blood, 2012, 119(19): 4441-4450.
49.	Clemente-Casares X, Blanco J, Ambalavanan P, et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature, 2016, 530(7591): 434-440.
50.	Cohen JL, Boyer O. The role of CD4⁺CD25^hi regulatory T cells in the physiopathogeny of graft-versus-host disease. Curr Opin ImmunolL, 2006, 18(5): 580-585.
51.	Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood, 2002, 99(15): 3493-3499.
52.	Edinger M, Hoffmann P, Ermann J, et al. CD4⁺CD25⁺ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med, 2003, 9(9): 1144-1150.
53.	Sagoo P, Ratnasothy K, Tsang Y, et al. Alloantigen-specific regulatory T cells prevent experimental chronic graft-versus-host disease by simultaneous control of allo- and autoreactivity. Eur J Immunol, 2012, 42(12): 3322-3333.
54.	Trenado A, Sudres M, Tang Q, et al. Ex vivo-expanded CD4⁺CD25⁺ immunoregulatory T cells prevent graft-versus-host-disease by inhibiting activation/differentiation of pathogenic T cells. J Immunol, 2006, 176(2): 1266-1273.
55.	Veerapathran A, Pidala J, Beato F, et al. Ex vivo expansion of human Tregs specific for alloantigens presented directly or indirectly. Blood, 2011, 118(20): 5671-5680.
56.	Koenecke C, Czeloth N, Bubke A, et al. Alloantigen-specific de novo-induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD. Eur J Immunol, 2009, 39(11): 3091-3096.
57.	Sagoo P, Ali N, Garg G, et al. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med, 2011, 3(83): 83ra42.
58.	Takasato F, Morita R, Schichita T, et al. Prevention of allogeneic cardiac graft rejection by transfer of ex vivo expanded antigen-specific regulatory T-cells. PLoS One, 2014, 9(2): e87722.
59.	Adair PR, Kim YC, Zhang AH et al. Human Tregs made antigen specific by gene modification: the power to treat autoimmunity and antidrug antibodies with precision. Front Immunol, 2017, 8: 1117.

1. Sakaguchi S. Naturally arising Foxp3-expressing CD25⁺CD4⁺ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol, 2005, 6(4): 345-352.
2. Sakaguchi S, Yamaguchi T, Nomura T, et al. Regulatory T cells and immune tolerance. Cell, 2008, 133(5): 775-787.
3. Tadokoro CE, Shakhar G, Shen SQ, et al. Regulatory T cells inhibit stable contacts between CD4(+) T cells and dendritic cells in vivo. J Exp Med, 2006, 203(3): 505-511.
4. Li CR, Baaten BJ, Bradley LM. Harnessing memory adaptive regulatory T cells to control autoimmunity in type 1 diabetes. J Mol Cell Biol, 2012, 4(1): 38-47.
5. Duran-Struuck R, Sondermeijer HP, Bühler L, et al. Effect of ex vivo-expanded recipient regulatory T cells on hematopoietic chimerism and kidney allograft tolerance across MHC barriers in cynomolgus macaques. Transplantation, 2017, 101(2): 274-283.
6. Heinrichs J, Bastian D, Veerapathran A, et al. Regulatory T-Cell therapy for graft-versus-host disease. J Immunol Res Ther, 2016, 1(1): 1-14.
7. Bluestone JA, Buckner JH, Fitch M, et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med, 2015, 7(315): 315ra189.
8. Hsieh CS, Liang Y, Tyznik AJ, et al. Recognition of the peripheral self by naturally arising CD25⁺ CD4⁺ T cell receptors. Immunity, 2004, 21(2): 267-277.
9. Sagoo P, Lombardi G, Lechler RI. Relevance of regulatory T cell promotion of donor-specific tolerance in solid organ transplantation. Front Immunol, 2012, 3(3): 184.
10. Tsaur I, Gasser M, Aviles B, et al. Donor antigen-specific regulatory T-cell function affects outcome in kidney transplant recipients. Kidney Int, 2011, 79(9): 1005-1012.
11. Hoffmann P, Eder R, Edinger M. Polyclonal expansion of human CD4(+)CD25(+) regulatory T cells. Methods Mol Biol, 2011, 677: 15-30.
12. Pilat N, Klaus C, Gattringer M, et al. Therapeutic efficacy of polyclonal tregs does not require rapamycin in a low-dose irradiation bone marrow transplantation model. Transplantation, 2011, 92(3): 280-288.
13. Zwar TD, Read S, van Driel IR, et al. CD4⁺CD25⁺ regulatory T cells inhibit the antigen-dependent expansion of self-reactive T cells in vivo. J Immunol, 2006, 176(3): 1609-1617.
14. Cheraï M, Hamel Y, Baillou C, et al. Generation of human alloantigen-specific regulatory T cells under good manufacturing practice-compliant conditions for cell therapy. Cell Transplant, 2015, 24(12): 2527-2540.
15. Hoffmann P, Eder R, Edinger M. Polyclonal expansion of human CD4(+)CD25(+) regulatory T cells. Methods Mol Biol, 2011, 677: 15-30.
16. He X, Smeets RL, van Rijssen E, et al. Single CD28 stimulation induces stable and polyclonal expansion of human regulatory T cells. Sci Rep, 2017, 7(7): 43003.
17. Thornton AM, Shevach EM. CD4⁺CD25⁺ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med, 1998, 188(2): 287-296.
18. Jin X, Wang Y, Hawthorne WJ, et al. Enhanced suppression of the xenogeneic T-cell response in vitro by xenoantigen stimulated and expanded regulatory T cells. Transplantation, 2014, 97(1): 30-38.
19. Jeffery HC, Jeffery LE, Lutz P, et al. Low-dose interleukin-2 promotes STAT-5 phosphorylation, Treg survival and CTLA-4-dependent function in autoimmune liver diseases. Clin Exp Immunol, 2017, 188(3): 394-411.
20. Peters JH, Hilbrands LB, Koenen HJ, et al. Ex vivo Generation of human alloantigen-specific regulatory T cells from CD4(pos)CD25(high) T cells for immunotherapy. PLoS One, 2008, 3(5): e2233.
21. Jiang S, Tsang J, Game DS, et al. Generation and expansion of human CD4⁺ CD25⁺ regulatory T cells with indirect allospecificity: Potential reagents to promote donor-specific transplantation tolerance. Transplantation, 2006, 82(12): 1738-1743.
22. Wiesinger M, Stoica D, Roessner S et al. Good manufacturing practice-compliant production and lot-release of ex vivo expanded regulatory T cells as basis for treatment of patients with autoimmune and inflammatory disorders. Front Immunol, 2017, 8: 1371.
23. Novak EJ, Masewicz SA, Liu AW, et al. Activated human epitope-specific T cells identified by class Ⅱ tetramers reside within a CD4^high, proliferating subset. Int Immunol, 2001, 13(6): 799-806.
24. Jin X, Lu Y, Zhao Y, et al. Large-scale in vitro expansion of human regulatory T cells with potent xenoantigen-specific suppression. Cytotechnology, 2016, 68(4): 935-945.
25. Yamazaki S, Patel M, Harper A, et al. Effective expansion of alloantigen-specific Foxp3⁺ CD25⁺ CD4⁺ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc Natl Acad Sci USA, 2006, 103(8): 2758-2763.
26. Litjens NH, Boer K, Zuijderwijk JM, et al. Allogeneic mature human dendritic cells generate superior alloreactive regulatory T cells in the presence of IL-15. J Immunol, 2015, 194(11): 5282-5293.
27. Fisson S, Djelti F, Trenado A, et al. Therapeutic potential of self-antigen-specific CD4⁺ CD25⁺ regulatory T cells selected in vitro from a polyclonal repertoire. Eur J Immunol, 2006, 36(4): 817-827.
28. Chen WJ, Jin WW, Hardegen N, 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(12): 1875-1886.
29. Fantini MC, Becker C, Monteleone G, et al. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol, 2004, 172(9): 5149-5153.
30. Long SA, Walker MR, Rieck M, et al. Functional islet-specific Treg can be generated from CD4+CD25- T cells of healthy and type 1 diabetic subjects. Eur J Immunol, 2009, 39(2): 612-620.
31. Tu W, Lau YL, Zheng J, et al. Efficient Generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells. Blood, 2008, 112(6): 2554-2562.
32. Zheng J, Liu Y, Qin G, et al. Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells. J Immunol, 2009, 183(6): 3742-3750.
33. Fourcade J, Sun Z, Kudela P, et al. Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire. J Immunol, 2010, 184(12): 6709-6718.
34. Wu J, Hu M, Qian YW, et al. In vivo costimulation-blockade induced regulatory T cells demonstrate dominant and specific tolerance to porcine islet-xenografts. Transplantation, 2017, 101(7): 1587-1599.
35. Jordan MS, Boesteanu A, Reed AJ, et al. Thymic selection of CD4⁺CD25⁺ regulatory T cells induced by an agonist self-peptide. Nat Immunol, 2001, 2(4): 301-306.
36. Kronenberg M, Rudensky A. Regulation of immunity by self-reactive T cells. Nature, 2005, 435(742): 598-604.
37. Spence A, Tang QZ. Restoring regulatory T cells in type 1 diabetes. Curr Diab Rep, 2016, 16(11): 110.
38. Karim M, Feng G, Wood KJ, et al. CD25⁺CD4⁺ regulatory T cells generated by exposure to a model protein antigen prevent allograft rejection: antigen-specific reactivation in vivo is critical for bystander regulation. Blood, 2005, 105(12): 4871-4877.
39. Yi S, Ji M, Wu J, et al. Adoptive transfer with in vitro expanded human regulatory T cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice. Diabetes, 2012, 61(5): 1180-1191.
40. Tang Q, Adams JY, Tooley AJ, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol, 2006, 7(1): 83-92.
41. Miller MJ, Safrina O, Parker I, et al. Imaging the single cell dynamics of CD4⁺ T cell activation by dendritic cells in lymph nodes. J Exp Med, 2004, 200(7): 847-856.
42. Stoll S, Delon J, Brotz TM, et al. Dynamic imaging of T cell-dendritic cell interactions in lymph nodes. Science, 2002, 296(5574): 1873-1876.
43. Germain RN, Miller MJ, Dustin ML, et al. Dynamic imaging of the immune system: progress, pitfalls and promise. Nat Rev Immunol, 2006, 6(7): 497-507.
44. Kukreja A, Cost G, Marker J, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest, 2002, 109(1): 131-140.
45. Perri V, Russo B, Crinò A, et al. Expression of PD-1 molecule on regulatory T lymphocytes in patients with insulin-dependent diabetes mellitus. Int J Mol Sci, 2015, 16(9): 22584-22605.
46. Tang QZ, Henriksen KJ, Bi MY, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med, 2004, 199(11): 1455-1465.
47. Masteller EL, Warner MR, Tang Q, et al. Expansion of functional endogenous antigen-specific CD4⁺CD25⁺ regulatory T cells from nonobese diabetic mice. J Immunol, 2005, 175(5):3053-3059.
48. Tran GT, Hodgkinson SJ, Carter NM, et al. IL-5 promotes induction of antigen-specific CD4⁺CD25⁺ T regulatory cells that suppress autoimmunity. Blood, 2012, 119(19): 4441-4450.
49. Clemente-Casares X, Blanco J, Ambalavanan P, et al. Expanding antigen-specific regulatory networks to treat autoimmunity. Nature, 2016, 530(7591): 434-440.
50. Cohen JL, Boyer O. The role of CD4⁺CD25^hi regulatory T cells in the physiopathogeny of graft-versus-host disease. Curr Opin ImmunolL, 2006, 18(5): 580-585.
51. Taylor PA, Lees CJ, Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood, 2002, 99(15): 3493-3499.
52. Edinger M, Hoffmann P, Ermann J, et al. CD4⁺CD25⁺ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med, 2003, 9(9): 1144-1150.
53. Sagoo P, Ratnasothy K, Tsang Y, et al. Alloantigen-specific regulatory T cells prevent experimental chronic graft-versus-host disease by simultaneous control of allo- and autoreactivity. Eur J Immunol, 2012, 42(12): 3322-3333.
54. Trenado A, Sudres M, Tang Q, et al. Ex vivo-expanded CD4⁺CD25⁺ immunoregulatory T cells prevent graft-versus-host-disease by inhibiting activation/differentiation of pathogenic T cells. J Immunol, 2006, 176(2): 1266-1273.
55. Veerapathran A, Pidala J, Beato F, et al. Ex vivo expansion of human Tregs specific for alloantigens presented directly or indirectly. Blood, 2011, 118(20): 5671-5680.
56. Koenecke C, Czeloth N, Bubke A, et al. Alloantigen-specific de novo-induced Foxp3⁺ Treg revert in vivo and do not protect from experimental GVHD. Eur J Immunol, 2009, 39(11): 3091-3096.
57. Sagoo P, Ali N, Garg G, et al. Human regulatory T cells with alloantigen specificity are more potent inhibitors of alloimmune skin graft damage than polyclonal regulatory T cells. Sci Transl Med, 2011, 3(83): 83ra42.
58. Takasato F, Morita R, Schichita T, et al. Prevention of allogeneic cardiac graft rejection by transfer of ex vivo expanded antigen-specific regulatory T-cells. PLoS One, 2014, 9(2): e87722.
59. Adair PR, Kim YC, Zhang AH et al. Human Tregs made antigen specific by gene modification: the power to treat autoimmunity and antidrug antibodies with precision. Front Immunol, 2017, 8: 1117.

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