The IL-2/IL-2R system: From basic science to therapeutic applications to enhance immune regulation

Immunologic Research

Volumn 57, Issue 1-3, 2013, Pages 197-209

  Bayer, Allison L ^a   Pugliese, Alberto ^a   Malek, Thomas R ^a  

^a UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

Author keywords

Autoimmunity; IL 2; Insulin; Tolerance; Treg cells; Type 1 diabetes

Indexed keywords

INTERLEUKIN 2; INTERLEUKIN 2 RECEPTOR; T LYMPHOCYTE RECEPTOR;

ARTICLE; CELL MATURATION; CLINICAL TRIAL (TOPIC); GRAFT RECIPIENT; HOMEOSTASIS; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; IMMUNOTHERAPY; INSULIN DEPENDENT DIABETES MELLITUS; LOW DRUG DOSE; PATHOGENESIS; PRIORITY JOURNAL; RECURRENT DISEASE; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION;

ADOPTIVE TRANSFER; ANIMALS; CLINICAL TRIALS AS TOPIC; DIABETES MELLITUS, TYPE 1; HOMEOSTASIS; HUMANS; IMMUNOMODULATION; IMMUNOTHERAPY; INTERLEUKIN-2; ISOANTIGENS; RECEPTORS, INTERLEUKIN-2; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, REGULATORY; TRANSLATIONAL MEDICAL RESEARCH;

EID: 84891488474     PISSN: 0257277X     EISSN: 15590755     Source Type: Journal    
DOI: 10.1007/s12026-013-8452-5     Document Type: Article

References (98)

1. Malek TR the biology of interleukin-2. Annu Rev Immunol. 2008;26:453-79.
2. Nelson BH, Willerford DM. Biology of the interleukin-2 receptor. Adv Immunol. 1998;70:1-81.
3. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell. 1993;75(2):253-61.
4. Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, Matsuyama T, et al. Deregulated T cell activation and autoimmunity in mice lacking interleulin 2 receptor β. Science. 1995;268(5216):1472-6.
5. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW. Interleukin-2 receptor α-chain regulates the size and content of the peripheral lymphoid compartment. Immunity. 1995;3(4):521-30.
6. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol. 2004;4(9):665-74.
7. Malek TR, Porter BO, Codias EK, Scibelli P, Yu A. Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors. J Immunol. 2000;164(6):2905-14.
8. Malek TR, Yu A, Vincek V, Scibelli P, Kong L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice. Implications for the nonredundant function of IL-2. Immunity. 2002;17(2):167-78.
9. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057-61.
10. + regulatory T cells in the absence of interleukin 2 signaling. Nat Immunol. 2005;6(11):1152-9.
11. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6(11):1142-51.
12. + T regulatory cells. J Immunol. 2007;178(7):4062-71.
13. Cheng G, Yu A, Dee MJ, Malek TR. IL-2R signaling is essential for functional maturation of regulatory T cells during thymic development. J Immunol. 2013;190(4):1567-75.
14. Burchill MA, Yang J, Vang KB, Moon JJ, Chu HH, Lio CW, et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity. 2008;28(1):112-21.
15. + regulatory T cells. J Immunol. 2007;178(1):280-90.
16. Lio CW, Hsieh CS. A two-step process for thymic regulatory T cell development. Immunity. 2008;28(1):100-11.
17. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity. 2009;30(5):616-25.
18. + T regulatory cells. J Immunol. 2008;181(1):225-34.
19. + regulatory T cell development. J Immunol. 2008;181(5):3285-90.
20. + T regulatory cells. J Immunol. 2006;177(8):5115-21.
21. Yu A, Zhu L, Altman NH, Malek TR. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity. 2009;30(2):204-17.
22. + T regulatory cell development during the neonatal period. J Exp Med. 2005;201(5):769-77.
23. + regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med. 2005;201(5):723-35.
24. Chougnet CA, Tripathi P, Lages CS, Raynor J, Sholl A, Fink P, et al. A major role for Bim in regulatory T cell homeostasis. J Immunol. 2011;186(1):156-63.
25. + regulatory T cells. Nat Immunol. 2013;14(9):959-65.
26. + terminally differentiated T regulatory cells. J Immunol. 2012;189(4):1780-91.
27. + T regulatory cells. J Immunol. 2007;178(7):4022-6.
28. + regulatory T cells and for expansion of these cells. J Immunol. 2007;178(4):2018-27.
29. + T regulatory cells suppress autoimmunity while establishing transplantation tolerance. J Immunol. 2006;176(12):7149-53.
30. Adeegbe D, Levy RB, Malek TR. Allogeneic T regulatory cell-mediated transplantation tolerance in adoptive therapy depends on dominant peripheral suppression and central tolerance. Blood. 2010;115(10):1932-40.
31. + T regulatory cells with limited TCR diversity in control of autoimmunity. J Immunol. 2010;184(1):56-66.
32. Pugliese A the multiple origins of Type 1 diabetes. Diabet Med. 2013;30(2):135-46.
33. Pociot F, Akolkar B, Concannon P, Erlich HA, Julier C, Morahan G, et al. Genetics of type 1 diabetes: what's next? Diabetes. 2010;59(7):1561-71.
34. Barker JM, Barriga KJ, Yu L, Miao D, Erlich HA, Norris JM, et al. Prediction of autoantibody positivity and progression to type 1 diabetes: diabetes autoimmunity study in the young (DAISY). J Clin Endocrinol Metab. 2004;89(8):3896-902.
35. Campbell-Thompson ML, Atkinson MA, Butler AE, Chapman NM, Frisk G, Gianani R, et al the diagnosis of insulitis in human type 1 diabetes. Diabetologia. 2013;56(11):2541-3.
36. Coppieters KT, Amirian N, Pagni PP, Baca Jones C, Wiberg A, Lasch S, et al. Functional redundancy of CXCR3/CXCL10 signaling in the recruitment of diabetogenic cytotoxic T lymphocytes to pancreatic islets in a virally induced autoimmune diabetes model. Diabetes. 2013;62(7):2492-9.
37. Ziegler AG, Rewers M, Simell O, Simell T, Lempainen J, Steck A, et al. Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA. 2013;309(23):2473-9.
38. Roep BO, Peakman M. Diabetogenic T lymphocytes in human Type 1 diabetes. Curr Opin Immunol. 2011;23(6):746-53.
39. Derbinski J, Kyewski B. How thymic antigen presenting cells sample the body's self-antigens. Curr Opin Immunol. 2010;22(5):592-600.
40. Pugliese A, Zeller M, Fernandez A Jr, Zalcberg LJ, Bartlett RJ, Ricordi C, et al the insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet. 1997;15(3):293-7.
41. Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet. 1997;15(3):289-92.
42. Pugliese A. Insulin: a critical autoantigen and potential therapeutic agent in Type 1 diabetes. Expert Rev Clin Immunol. 2006;2(3):419-31.
43. Nakayama M, Abiru N, Moriyama H, Babaya N, Liu E, Miao D, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature. 2005;435(7039):220-3.
44. de Jong VM, Abreu JR, Verrijn Stuart AA, van der Slik AR, Verhaeghen K, Engelse MA, et al. Alternative splicing and differential expression of the islet autoantigen IGRP between pancreas and thymus contributes to immunogenicity of pancreatic islets but not diabetogenicity in humans. Diabetologia. 2013. doi: 10.1007/s00125-013-3034-6.
45. Diez J, Park Y, Zeller M, Brown D, Garza D, Ricordi C, et al. Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen. Diabetes. 2001;50(4):895-900.
46. Dogra RS, Vaidyanathan P, Prabakar KR, Marshall KE, Hutton JC, Pugliese A. Alternative splicing of G6PC2, the gene coding for the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), results in differential expression in human thymus and spleen compared with pancreas. Diabetologia. 2006;49(5):953-7.
47. Durinovic-Bello I, Wu RP, Gersuk VH, Sanda S, Shilling HG, Nepom GT. Insulin gene VNTR genotype associates with frequency and phenotype of the autoimmune response to proinsulin. Genes Immun. 2010;11(2):188-93.
48. Akiyama T, Shinzawa M, Qin J, Akiyama N. Regulations of gene expression in medullary thymic epithelial cells required for preventing the onset of autoimmune diseases. Front Immunol. 2013;4:249.
49. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298(5597):1395-401.
50. Pugliese A, Brown D, Garza D, Murchison D, Zeller M, Redondo MJ, et al. Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. J Clin Invest. 2001;107(5):555-64.
51. Garcia CA, Prabakar KR, Diez J, Cao ZA, Allende G, Zeller M, et al. Dendritic cells in human thymus and periphery display a proinsulin epitope in a transcription-dependent, capture-independent fashion. J Immunol. 2005;175(4):2111-22.
52. Zhu M, Chin RK, Christiansen PA, Lo JC, Liu X, Ware C, et al. NF-kappaB2 is required for the establishment of central tolerance through an aire-dependent pathway. J Clin Invest. 2006;116(11):2964-71.
53. Poliani PL, Kisand K, Marrella V, Ravanini M, Notarangelo LD, Villa A, et al. Human peripheral lymphoid tissues contain autoimmune regulator-expressing dendritic cells. Am J Pathol. 2010;176(3):1104-12.
54. + tolerogenic dendritic cells in maintaining peripheral self-tolerance of islet beta-cells. Cell Immunol. 2012;273(2):115-23.
55. Gardner JM, Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, et al. Deletional tolerance mediated by extrathymic aire-expressing cells. Science. 2008;321(5890):843-7.
56. + T Cells. Immunity. 2013;39(3):560-72.
57. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via aire-independent direct antigen presentation. J Exp Med. 2010;207(4):681-8.
58. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010;207(4):689-97.
59. Anderson MS, Bluestone JA the NOD mouse: a model of immune dysregulation. Annu Rev Immunol. 2005;23:447-85.
60. Kodama K, Butte AJ, Creusot RJ, Su L, Sheng D, Hartnett M, et al. Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice. Clin Immunol. 2008;129(2):195-201.
61. von Herrath M, Peakman M, Roep B. Progress in immune-based therapies for type 1 diabetes. Clin Exp Immunol. 2013;172(2):186-202.
62. Hagopian W, Ferry RJ, Jr., Sherry N, Carlin D, Bonvini E, Johnson S, et al. Teplizumab preserves C-peptide in recent-onset type 1 diabetes: 2-year results from the randomized, placebo-controlled Protege trial. Diabetes. 2013;62(11):3901-8.
63. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143-52.
64. Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 2011;378(9789):412-9.
65. Burke GW III, Vendrame F, Pileggi A, Ciancio G, Reijonen H, Pugliese A. Recurrence of autoimmunity following pancreas transplantation. Curr Diab Rep. 2011;11(5):413-9.
66. Vendrame F, Pileggi A, Laughlin E, Allende G, Martin-Pagola A, Molano RD, et al. Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells. Diabetes. 2010;59(4):947-57.
67. + T cells in autoimmune diabetes after pancreas transplantation. Clin Immunol. 2008;128(1):23-30.
68. Monti P, Heninger AK, Bonifacio E. Differentiation, expansion, and homeostasis of autoreactive T cells in type 1 diabetes mellitus. Curr Diab Rep. 2009;9(2):113-8.
69. Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R, et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet. 2007;39(9):1074-82.
70. + regulatory T cell function. J Immunol. 2012;188(9):4644-53.
71. + regulatory T cells. J Immunol. 2008;181(10):7350-5.
72. Yamanouchi J, Rainbow D, Serra P, Howlett S, Hunter K, Garner VE, et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet. 2007;39(3):329-37.
73. Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity. 2008;28(5):687-97.
74. Grinberg-Bleyer Y, Baeyens A, You S, Elhage R, Fourcade G, Gregoire S, et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J Exp Med. 2010;207(9):1871-8.
75. + regulatory T cells from nonobese diabetic mice. J Immunol. 2005;175(5):3053-9.
76. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004;199(11):1455-65.
77. + T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med. 2004;199(11):1467-77.
78. Abrams D, Levy Y, Losso MH, Babiker A, Collins G, Cooper DA, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361(16):1548-59.
79. + regulatory T cells in cancer patients. Blood. 2006;107(6):2409-14.
80. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127(4):759-67.
81. Webster KE, Walters S, Kohler RE, Mrkvan T, Boyman O, Surh CD, 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):751-60.
82. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP III, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22):2055-66.
83. Matsuoka K, Koreth J, Kim HT, Bascug G, McDonough S, Kawano Y, 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):179ra43.
84. Saadoun D, Rosenzwajg M, Joly F, Six A, Carrat F, Thibault V, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365(22):2067-77.
85. Long SA, Rieck M, Sanda S, Bollyky JB, Samuels PL, Goland R, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs beta-cell function. Diabetes. 2012;61(9):2340-8.
86. Baeyens A, Perol L, Fourcade G, Cagnard N, Carpentier W, Woytschak J, et al. Limitations of IL-2 and rapamycin in immunotherapy of type 1 diabetes. Diabetes. 2013;62(9):3120-31.
87. Hartemann A, Bensimon G, Payan CA, Jacqueminet S, Bourron O, Nicolas N, et al. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2013. doi: 10.1016/S2213-8587(13)70113-X.
88. Ludvigsson J, Faresjo M, Hjorth M, Axelsson S, Cheramy M, Pihl M, et al. GAD treatment and insulin secretion in recent-onset type 1 diabetes. N Engl J Med. 2008;359(18):1909-20.
89. Ludvigsson J, Krisky D, Casas R, Battelino T, Castano L, Greening J, et al. GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N Engl J Med. 2012;366(5):433-42.
90. Michels AW, von Herrath M. 2011 update: antigen-specific therapy in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2011;18(4):235-40.
91. Nanto-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, et al. Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and autoantibodies conferring increased risk of disease: a double-blind, randomised controlled trial. Lancet. 2008;372(9651):1746-55.
92. Roep BO, Solvason N, Gottlieb PA, Abreu JR, Harrison LC, Eisenbarth GS, et al. Plasmid-encoded proinsulin preserves C-peptide while specifically reducing proinsulin-specific CD8(+) T cells in type 1 diabetes. Sci Transl Med. 2013;5(191):191ra82.
93. Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, et al. Effects of oral insulin in relatives of patients with type 1 diabetes: the diabetes prevention trial - type 1. Diabetes Care. 2005;28(5):1068-76.
94. Vehik K, Cuthbertson D, Ruhlig H, Schatz DA, Peakman M, Krischer JP. Long-term outcome of individuals treated with oral insulin: diabetes prevention trial-type 1 (DPT-1) oral insulin trial. Diabetes Care. 2011;34(7):1585-90.
95. Marek-Trzonkowska N, Mysliwec M, Siebert J, Trzonkowski P. Clinical application of regulatory T cells in type 1 diabetes. Pediatr Diabetes. 2013;14(5):322-32.
96. Marek-Trzonkowska N, Mysliwiec M, Dobyszuk A, Grabowska M, Techmanska I, Juscinska J, et al. Administration of CD4+ CD25 high CD127-regulatory T cells preserves beta-cell function in type 1 diabetes in children. Diabetes Care. 2012;35(9):1817-20.
97. Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes. 2009;58(3):652-62.
98. Cabello C, Pugliese A, Pileggi A, Bayer A. Immunology/transplantation. Diabetes. 2013;62(Supplement 1):A438-53. doi: 10.2337/db13-1678-1742.