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 CD4high, 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+CD25hi 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 CD4high, 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+CD25hi 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.