Natural variation in interleukin-2 sensitivity influences regulatory T-cell frequency and function in individuals with long-standing type 1 diabetes

Diabetes

Volumn 64, Issue 11, 2015, Pages 3891-3902

  Yang, Jennie H M ^a,b   Cutler, Antony J ^c   Ferreira, Ricardo C ^c   Reading, James L ^a,b   Cooper, Nicholas J ^c   Wallace, Chris ^c   Clarke, Pamela ^c   Smyth, Deborah J ^c   Boyce, Christopher S ^d   Gao, Guo Jian ^d   Todd, John A ^c   Wicker, Linda S ^c   Tree, Timothy I M ^a,b  

^a KING'S COLLEGE LONDON   (United Kingdom)

^b GUY'S AND ST THOMAS' NHS FOUNDATION TRUST   (United Kingdom)

^c UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^d BD BIOSCIENCES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 2; STAT5A PROTEIN; TRANSCRIPTION FACTOR FOXP3; IL2RA PROTEIN, HUMAN; INTERLEUKIN 2 RECEPTOR ALPHA; NON RECEPTOR PROTEIN TYROSINE PHOSPHATASE 2; PTPN2 PROTEIN, HUMAN;

ADULT; ARTICLE; CD4+ T LYMPHOCYTE; CONTROLLED STUDY; GENE; GENETIC POLYMORPHISM; HUMAN; HUMAN CELL; IMMUNOTHERAPY; INSULIN DEPENDENT DIABETES MELLITUS; MAJOR CLINICAL STUDY; PHENOTYPE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; PTPN2 GENE; REGULATORY T LYMPHOCYTE; T LYMPHOCYTE SUBPOPULATION; DRUG EFFECTS; GENETICS; GENOTYPE; IMMUNOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM;

DIABETES MELLITUS, TYPE 1; GENOTYPE; HUMANS; INTERLEUKIN-2; INTERLEUKIN-2 RECEPTOR ALPHA SUBUNIT; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEIN TYROSINE PHOSPHATASE, NON-RECEPTOR TYPE 2; SIGNAL TRANSDUCTION; T-LYMPHOCYTES, REGULATORY;

EID: 84962164171     PISSN: 00121797     EISSN: 1939327X     Source Type: Journal    
DOI: 10.2337/db15-0516     Document Type: Article

References (46)

1. Wellcome Trust Case Control Consortium. Genome-wide association study of 14, 000 cases of seven common diseases and 3, 000 shared controls. Nature 2007;447:661-678
2. Barrett JC, Clayton DG, Concannon P, et al.; Type 1 Diabetes Genetics Consortium. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 2009;41:703-707
3. Todd JA, Walker NM, Cooper JD, et al.; Genetics of Type 1 Diabetes in Finland; Wellcome Trust Case Control Consortium. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007;39:857-864
4. Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes 2005;54:1407-1414
5. Glisic-Milosavljevic S, Waukau J, Jailwala P, et al. At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+ T-cell fraction. PLoS One 2007;2:e146
6. Jailwala P, Waukau J, Glisic S, et al. Apoptosis of CD4+ CD25 (high) T cells in type 1 diabetes may be partially mediated by IL-2 deprivation. PLoS One 2009;4:e6527
7. Lawson JM, Tremble J, Dayan C, et al. Increased resistance to CD4+CD25hi regulatory T cell-mediated suppression in patients with type 1 diabetes. Clin Exp Immunol 2008;154:353-359
8. Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI. Defective suppressor function in CD4 (+) CD25 (+) T-cells from patients with type 1 diabetes. Diabetes 2005;54:92-99
9. Cerosaletti K, Schneider A, Schwedhelm K, et al. Multiple autoimmuneassociated variants confer decreased IL-2R signaling in CD4+ CD25 (hi) T cells of type 1 diabetic and multiple sclerosis patients. PLoS One 2013;8:e83811
10. Long SA, Cerosaletti K, Bollyky PL, et al. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4 (+) CD25 (+) regulatory T-cells of type 1 diabetic subjects. Diabetes 2010;59:407-415
11. Hughson A, Bromberg I, Johnson B, Quataert S, Jospe N, Fowell DJ. Uncoupling of proliferation and cytokines from suppression within the CD4+CD25+Foxp3+ T-cell compartment in the 1st year of human type 1 diabetes. Diabetes 2011;60:2125-2133
12. Bayer AL, Yu A, Adeegbe D, Malek TR. Essential role for interleukin-2 for CD4 (+) CD25 (+) T regulatory cell development during the neonatal period. J Exp Med 2005;201:769-777
13. Burchill MA, Yang J, Vang KB, Farrar MA. Interleukin-2 receptor signaling in regulatory T cell development and homeostasis. Immunol Lett 2007;114:1-8
14. Malek TR, Bayer AL. Tolerance, not immunity, crucially depends on IL-2. Nat Rev Immunol 2004;4:665-674
15. Setoguchi R, Hori S, Takahashi T, Sakaguchi S. Homeostatic maintenance of natural Foxp3 (+) CD25 (+) CD4 (+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005;201:723-735
16. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol 2005;6:1142-1151
17. Garg G, Tyler JR, Yang JH, et al. Type 1 diabetes-associated IL2RA variation lowers IL-2 signaling and contributes to diminished CD4+CD25+ regulatory T cell function. J Immunol 2012;188:4644-4653
18. Long SA, Cerosaletti K, Wan JY, et al. An autoimmune-associated variant in PTPN2 reveals an impairment of IL-2R signaling in CD4 (+) T cells. Genes Immun 2011;12:116-125
19. Dendrou CA, Plagnol V, Fung E, et al. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat Genet 2009;41:1011-1015
20. 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;30:204-217
21. Yu A, Snowhite I, Vendrame F, et al. Selective IL-2 responsiveness of regulatory T cells through multiple intrinsic mechanisms support the use of lowdose IL-2 therapy in type 1 diabetes. Diabetes 2015;64:2172-2183
22. Pekalski ML, Ferreira RC, Coulson RM, et al. Postthymic expansion in human CD4 naive T cells defined by expression of functional high-affinity IL-2 receptors. J Immunol 2013;190:2554-2566
23. Grinberg-Bleyer Y, Baeyens A, You 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;207:1871-1878
24. Tang Q, Adams JY, Penaranda C, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 2008;28:687-697
25. Matsuoka K, Koreth J, Kim HT, et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 2013;5:179ra43
26. Kennedy-Nasser AA, Ku S, Castillo-Caro P, et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin Cancer Res 2014;20:2215-2225
27. Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to lowdose interleukin-2 in HCV-induced vasculitis. N Engl J Med 2011;365:2067-2077
28. Castela E, Le Duff F, Butori C, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol 2014;150:748-751
29. Hartemann A, Bensimon G, Payan CA, et al. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebocontrolled trial. Lancet Diabetes Endocrinol 2013;1:295-305
30. Rosenzwajg M, Churlaud G, Mallone R, et al. Low-dose interleukin-2 fosters a dose-dependent regulatory T cell tuned milieu in T1D patients. J Autoimmun 2015;58:48-58
31. Waldron-Lynch F, Kareclas P, Irons K, et al. Rationale and study design of the Adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): a nonrandomised, open label, adaptive dose finding trial. BMJ Open 2014;4:e005559
32. Arif S, Leete P, Nguyen V, et al. Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes 2014;63:3835-3845
33. Ferreira RC, Simons HZ, Thompson WS, et al. IL-21 production by CD4+ effector T cells and frequency of circulating follicular helper T cells are increased in type 1 diabetes patients. Diabetologia 2015;58:781-790
34. Kenefeck R, Wang CJ, Kapadi T, et al. Follicular helper T cell signature in type 1 diabetes. J Clin Invest 2015;125:292-303
35. Thompson WS, Pekalski ML, Simons HZ, et al. Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes. Clin Exp Immunol 2014;177:571-585
36. Long SA, Rieck M, Sanda S, et al.; Diabetes TrialNet and the Immune Tolerance Network. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs b-cell function. Diabetes 2012;61:2340-2348
37. Krutzik PO, Nolan GP. Fluorescent cell barcoding in flow cytometry allows highthroughput drug screening and signaling profiling. Nat Methods 2006;3:361-368
38. Glisic S, Jailwala P. Interaction between Treg apoptosis pathways, Treg function and HLA risk evolves during type 1 diabetes pathogenesis. PLoS One 2012;7:e36040
39. Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009;30:899-911
40. Booth NJ, McQuaid AJ, Sobande T, et al. Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J Immunol 2010;184:4317-4326
41. Passerini L, Allan SE, Battaglia M, et al. STAT5-signaling cytokines regulate the expression of FOXP3 in CD4+CD25+ regulatory T cells and CD4+CD25-effector T cells. Int Immunol 2008;20:421-431
42. Williams LM, Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol 2007;8:277-284
43. Schneider A, Rieck M, Sanda S, Pihoker C, Greenbaum C, Buckner JH. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J Immunol 2008;181:7350-7355
44. Attridge K, Wang CJ, Wardzinski L, et al. IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis. Blood 2012;119:4656-4664
45. Xu X, Shi Y, Cai Y, et al. Inhibition of increased circulating Tfh cell by anti-CD20 monoclonal antibody in patients with type 1 diabetes. PLoS One 2013;8:e79858
46. Ito S, Bollard CM, Carlsten M, et al. Ultra-low dose interleukin-2 promotes immune-modulating function of regulatory T cells and natural killer cells in healthy volunteers. Mol Ther 2014;22:1388-1395