Harnessing FOXP3+ regulatory T cells for transplantation tolerance

Journal of Clinical Investigation

Volumn 124, Issue 4, 2014, Pages 1439-1445

  Waldmann, Herman ^a   Hilbrands, Robert ^a   Howie, Duncan ^a   Cobbold, Stephen ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CD4 ANTIGEN; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FOXP3;

CELL LINEAGE; HUMAN; IMMUNOSUPPRESSIVE TREATMENT; METABOLISM; NONHUMAN; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; TRANSPLANTATION TOLERANCE;

ANIMALS; EPIGENESIS, GENETIC; FORKHEAD TRANSCRIPTION FACTORS; HUMANS; IMMUNOSUPPRESSION; MICE; RECEPTORS, ANTIGEN, T-CELL; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, REGULATORY; TRANSPLANTATION TOLERANCE;

EID: 84897478690     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI67226     Document Type: Review

References (108)

1. Hall BM, Jelbart ME, Gurley KE, Dorsch SE. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. Mediation of specific suppression by T helper/inducer cells. J Exp Med. 1985;162(5):1683-1694. (Pubitemid 16195367)
2. Benjamin RJ, Waldmann H. Induction of tolerance by monoclonal antibody therapy. Nature. 1986;320(6061):4z 49-451.
3. Qin SX, Cobbold S, Benjamin R, Waldmann H. Induction of classical transplantation tolerance in the adult. J Exp Med. 1989;169(3):779-794. (Pubitemid 19085820)
4. Qin S, et al. "Infectious" transplantation tolerance. Science. 1993;259(5097):974-977.
5. Mason DW. Subsets of CD4+ T cells and their roles in autoimmunity. Philos Trans R Soc Lond B Biol Sci. 1993;342(1299):51-56.
6. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. 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. 1995;155(3):1151-1164.
7. Kim J, et al. Cutting edge: depletion of Foxp3+ cells leads to induction of autoimmunity by specific ablation of regulatory T cells in genetically targeted mice. J Immunol. 2009;183(12):7631-7634.
8. Kendal AR, et al. Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance. J Exp Med. 2011;208(10):2043- 2053.
9. Regateiro FS, et al. Foxp3 expression is required for the induction of therapeutic tissue tolerance. J Immunol. 2012;189(8):3947-3956.
10. Cobbold SP, Adams E, Marshall SE, Davies JD, Waldmann H. Mechanisms of peripheral tolerance and suppression induced by monoclonal antibodies to CD4 and CD8. Immunol Rev. 1996;149:5-33. (Pubitemid 26096976)
11. Davies JD, Leong LY, Mellor A, Cobbold SP, Waldmann H. T cell suppression in transplantation tolerance through linked recognition. J Immunol. 1996;156(10):3602-3607. (Pubitemid 26137645)
12. Wise MP, Bemelman F, Cobbold SP, Waldmann H. Linked suppression of skin graft rejection can operate through indirect recognition. J Immunol. 1998;161(11):5813-5816. (Pubitemid 28535944)
13. Groux H, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature. 1997;389(6652):737-742. (Pubitemid 27458961)
14. Passerini L, et al. Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. Eur J Immunol. 2011;41(4):1120-1131.
15. Oliveira VG, Agua-Doce A, Curotto de Lafaille MA, Lafaille JJ, Graca L. Adjuvant facilitates tolerance induction to factor VIII in hemophilic mice through a Foxp3-independent mechanism that relies on IL-10. Blood. 2013;121(19):3936-3945.
16. Sundstedt A, O'Neill EJ, Nicolson KS, Wraith DC. Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo. J Immunol. 2003;170(3):1240-1248. (Pubitemid 36139489)
17. Ng TH, Britton GJ, Hill EV, Verhagen J, Burton BR, Wraith DC. Regulation of adaptive immunity; the role of interleukin-10. Front Immunol. 2013;4:129.
18. Gregori S, Goudy KS, Roncarolo MG. The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells. Front Immunol. 2012;3:30.
19. Allan SE, et al. CD4+ T-regulatory cells: toward therapy for human diseases. Immunol Rev. 2008;223:391-421. (Pubitemid 351986179)
20. Bennett CL, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20-21. (Pubitemid 32044513)
21. Wildin RS, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27(1):18-20. (Pubitemid 32044512)
22. Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol. 2003;15(4):430-435. (Pubitemid 36774255)
23. + regulatory T cells: thymus or periphery. J Clin Invest. 2003;112(9):1310-1312.
24. Chaudhry A, Rudensky AY. Control of inflammation by integration of environmental cues by regulatory T cells. J Clin Invest. 2013;123(3):939-944.
25. + regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6(4):345-352.
26. + regulatory T cell-mediated immunosuppression. Cytokine Growth Factor Rev. 2003;14(2):85-89.
27. Sauer S, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A. 2008;105(22):7797-7802. (Pubitemid 351872718)
28. Powell JD, Heikamp EB, Pollizzi KN, Waickman AT. A modified model of T-cell differentiation based on mTOR activity and metabolism [published online ahead of print October 7, 2013]. Cold Spring Harb Symp Quant Biol. doi:10.1101/sqb.2013.78.020214.
29. Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H. mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature. 2013;499(7459):485-490.
30. Park Y, et al. TSC1 regulates the balance between effector and regulatory T cells. J Clin Invest. 2013;123(12):5165-5178.
31. Delgoffe GM, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12(4):295-303.
32. Liu G, Yang K, Burns S, Shrestha S, Chi H. The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat Immunol. 2010;11(11):1047-1056.
33. Josefowicz SZ, et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature. 2012;482(7385):395-399.
34. + regulatory T cell-mediated suppression of experimental graft-versus-host disease. J Immunol. 2010;185(7):3866-3872.
35. Tsang JY, et al. The potency of allospecific Tregs cells appears to correlate with T cell receptor functional avidity. Am J Transplant. 2011;11(8):1610-1620.
36. von Boehmer H, Daniel C. Therapeutic opportunities for manipulating T(Reg) cells in autoimmunity and cancer. Nat Rev Drug Discov. 2013;12(1):51-63.
37. Miyajima M, et al. Early acceptance of renal allografts in mice is dependent on foxp3(+) cells. Am J Pathol. 2011;178(4):1635-1645.
38. Benghiat FS, et al. Critical influence of natural regulatory CD25+ T cells on the fate of allografts in the absence of immunosuppression. Transplantation. 2005;79(6):648-654. (Pubitemid 40463170)
39. Neujahr DC, et al. Accelerated memory cell homeostasis during T cell depletion and approaches to overcome it. J Immunol. 2006;176(8):4632-4639.
40. Graca L, Le Moine A, Lin CY, Fairchild PJ, Cobbold SP, Waldmann H. Donor-specific transplantation tolerance: the paradoxical behavior of CD4+CD25+ T cells. Proc Natl Acad Sci U S A. 2004;101(27):10122-10126. (Pubitemid 38891205)
41. + regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol. 2004;172(10):6003-6010.
42. Daley SR, Ma J, Adams E, Cobbold SP, Waldmann H. A key role for TGF-beta signaling to T cells in the long-term acceptance of allografts. J Immunol. 2007;179(6):3648-3654.
43. Verginis P, McLaughlin KA, Wucherpfennig KW, von Boehmer H, Apostolou I. Induction of antigen-specific regulatory T cells in wild-type mice: visualization and targets of suppression. Proc Natl Acad Sci U S A. 2008;105(9):3479-3484. (Pubitemid 351723578)
44. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057-1061. (Pubitemid 36222930)
45. Andersen KG, Butcher T, Betz AG. Specific immunosuppression with inducible Foxp3-transduced polyclonal T cells. PLoS Biol. 2008;6(11):e276.
46. McMurchy AN, et al. A novel function for FOXP3 in humans: intrinsic regulation of conventional T cells. Blood. 2013;121(8):1265-1275.
47. Huang YJ, et al. Induced and thymus-derived Foxp3 regulatory T cells share a common niche. Eur J Immunol. 2014;44(2):460-468.
48. Liston A, Gray DH. Homeostatic control of regulatory T cell diversity [published online ahead of print January 31, 2014]. Nat Rev Immunol. doi:10.1038/nri3605.
49. Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol. 2007;7(8):585-598. (Pubitemid 47123554)
50. Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8(3):277-284. (Pubitemid 46745377)
51. Wan YY, Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature. 2007;445(7129):766-770. (Pubitemid 46279706)
52. Ohkura N, et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity. 2012;37(5):785-799.
53. Samstein RM, et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell. 2012;151(1):153-166.
54. + T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A. 2009;106(6):1903-1908.
55. 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. 2012;36(2):262-275.
56. Rubtsov YP, et al. Stability of the regulatory T cell lineage in vivo. Science. 2010;329(5999):1667-1671.
57. Bailey-Bucktrout SL, et al. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity. 2013;39(5):949-962.
58. Sakaguchi S, Vignali DA, Rudensky AY, Niec RE, Waldmann H. The plasticity and stability of regulatory T cells. Nat Rev Immunol. 2013;13(6):461-467.
59. Hori S. Regulatory T cell plasticity: beyond the controversies. Trends Immunol. 2011;32(7):295-300.
60. Chong AS, Alegre ML. The impact of infection and tissue damage in solid-organ transplantation. Nat Rev Immunol. 2012;12(6):459-471.
61. Floess S, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5(2):e38.
62. Toker A, et al. Active demethylation of the Foxp3 locus leads to the generation of stable regulatory T cells within the thymus. J Immunol. 2013;190(7):3180-3188.
63. Bruniquel D, Schwartz RH. Selective, stable demethylation of the interleukin-2 gene enhances transcription by an active process. Nat Immunol. 2003;4(3):235-240. (Pubitemid 36322132)
64. Michalek RD, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol. 2011;186(6):3299-3303.
65. Shi LZ, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011;208(7):1367-1376.
66. Chang CH, et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell. 2013;153(6):1239-1251.
67. Gubser PM, et al. Rapid effector function of memory CD8(+) T cells requires an immediate-early glycolytic switch. Nat Immunol. 2013;14(10):1064- 1072.
68. + T cell memory development. Immunity. 2012;36(1):68-78.
69. Dang EV, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146(5):772-784.
70. Fassett MS, Jiang W, D'Alise AM, Mathis D, Benoist C. Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion. Proc Natl Acad Sci U S A. 2012;109(10):3891-3896.
71. Waickman AT, Powell JD. mTOR, metabolism, and the regulation of T-cell differentiation and function. Immunol Rev. 2012;249(1):43-58.
72. Graca L, Cobbold SP, Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med. 2002;195(12):1641-1646. (Pubitemid 34666077)
73. Cobbold SP, et al. Immune privilege induced by regulatory T cells in transplantation tolerance. Immunol Rev. 2006;213:239-255. (Pubitemid 44401505)
74. Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell. 2012;150(1):29-38.
75. Andersen KG, Nissen JK, Betz AG. Comparative genomics reveals key gain-of-function events in Foxp3 during regulatory T cell evolution. Front Immunol. 2012;3:113.
76. Munn DH, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281(5380):1191-1193. (Pubitemid 28406294)
77. Cobbold SP, et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci U S A. 2009;106(29):12055- 12060.
78. Metz R, Duhadaway JB, Kamasani U, Laury-Kleintop L, Muller AJ, Prendergast GC. Novel tryptophan catabolic enzyme IDO2 is the preferred biochemical target of the antitumor indoleamine 2,3-dioxygenase inhibitory compound D-1-methyl-tryptophan. Cancer Res. 2007;67(15):7082-7087. (Pubitemid 47206533)
79. Fallarino F, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006;176(11):6752-6761. (Pubitemid 43787857)
80. Nowak EC, et al. Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J Exp Med. 2012;209(11):2127-2135.
81. Cobbold SP, Adams E, Nolan KF, Regateiro FS, Waldmann H. Connecting the mechanisms of T-cell regulation: dendritic cells as the missing link. Immunol Rev. 2010;236:203-218.
82. Cobbold SP, Adams E, Waldmann H. Biomarkers of transplantation tolerance: more hopeful than helpful? Front Immunol. 2011;2:9.
83. Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur J Immunol. 2013;43(4):889-896.
84. Deaglio S, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204(6):1257-1265. (Pubitemid 46919862)
85. Regateiro FS, et al. Generation of anti-inflammatory adenosine by leukocytes is regulated by TGF-β. Eur J Immunol. 2011;41(10):2955-2965.
86. Delgoffe GM, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity. 2009;30(6):832-844.
87. Cobbold SP. The mTOR pathway and integrating immune regulation [published online ahead of print August 19, 2013]. Immunology. doi:10.1111/imm.12162.
88. Heikamp EB, Powell JD. Sensing the immune microenvironment to coordinate T cell metabolism, differentiation and function. Semin Immunol. 2012;24(6):414-420.
89. Sawitzki B, et al. Prevention of graft-versus-host disease by adoptive T regulatory therapy is associated with active repression of peripheral blood toll-like receptor 5 mRNA expression. Biol Blood Marrow Transplant. 2014;20(2):173-182.
90. Hippen KL, et al. Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Transl Med. 2011;3(83):83ra41.
91. Tang Q, Bluestone JA. Regulatory T-cell therapy in transplantation: moving to the clinic. Cold Spring Harb Perspect Med. 2013;3(11):a015552.
92. McMurchy AN, Bushell A, Levings MK, Wood KJ. Moving to tolerance: clinical application of T regulatory cells. Semin Immunol. 2011;23(4):304-313.
93. Wu DC, et al. Ex vivo expanded human regulatory T cells can prolong survival of a human islet allograft in a humanized mouse model. Transplantation. 2013;96(8):707-716.
94. Putnam AL, et al. Clinical grade manufacturing of human alloantigen-reactive regulatory T cells for use in transplantation. Am J Transplant. 2013;13(11):3010-3020.
95. Edinger M. Regulatory T cells for the prevention of graft-versus-host disease: professionals defeat amateurs. Eur J Immunol. 2009;39(11):2966-2968.
96. Di Ianni M, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117(14):3921-3928.
97. Martelli MF, et al. "Designed" grafts for HLA-haploidentical stem cell transplantation. Blood. 2014;123(7):967-973.
98. Hansmann L, et al. Dominant Th2 differentiation of human regulatory T cells upon loss of FOXP3 expression. J Immunol. 2012;188(3):1275-1282.
99. Sagoo P, Ali N, Garg G, Nestle FO, Lechler RI, Lombardi G. 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.
100. Nadig SN, et al. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med. 2010;16(7):809-813.
101. Webster KE, et al. 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. 2009;206(4):751-760.
102. Boyman O, Sprent J. The role of interleukin-2 during homeostasis and activation of the immune system. Nat Rev Immunol. 2012;12(3):180-190.
103. Matsuoka K, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med. 2013;5(179):179ra143.
104. Tai X, et al. Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals. Immunity. 2013;38(6):1116-1128.
105. Scully R, Qin S, Cobbold S, Waldmann H. Mechanisms in CD4 antibody-mediated transplantation tolerance: kinetics of induction, antigen dependency and role of regulatory T cells. Eur J Immunol. 1994;24(10):2383-2392. (Pubitemid 24303082)
106. Marshall SE, Cobbold SP, Davies JD, Martin GM, Phillips JM, Waldmann H. Tolerance and suppression in a primed immune system. Transplantation. 1996;62(11):1614-1621. (Pubitemid 27009920)
107. Siepert A, et al. Permanent CNI treatment for prevention of renal allograft rejection in sensitized hosts can be replaced by regulatory T cells. Am J Transplant. 2012;12(9):2384-2394.
108. Wu Z, et al. Homeostatic proliferation is a barrier to transplantation tolerance. Nat Med. 2004;10(1):87-92. (Pubitemid 38524703)