The IL-2/CD25 pathway determines susceptibility to T1D in humans and NOD mice.
Although the interleukin-2 (IL-2)/IL-2R signaling pathway has been the focus of numerous studies, certain aspects of its molecular regulation are not well characterized, especially in non-T cells, and a more complete understanding of the pathway is necessary to discern the functional basis of the genetic association between the IL-2-IL-21 and IL-2RA/CD25 gene regions and T1D in humans. Genetic variation in these regions may promote T1D susceptibility by influencing transcription and/or splicing and, hence, IL-2 and IL-2RA/CD25 expression at the protein level in different immune cell subsets; thus, there is a need to establish links between the genetic variation and immune cell phenotypes and functions in humans, which can be further investigated and validated in mouse models. The detection and characterization of genetically determined immunophenotypes should aid in elucidating disease mechanisms and may enable future monitoring of disease initiation and progression in prediabetic subjects and of responses to therapeutic intervention.
Dendrou
Calliope A
CA
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, CB2 OXY, UK.
Wicker
Linda S
LS
D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D015551:Autoimmunity; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D055611:Natural Killer T-Cells / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit
J Clin Invest. 1993 Jun;91(6):2504-12
7685771
Cytokine Growth Factor Rev. 1997 Dec;8(4):313-32
9620644
Nat Genet. 1999 Feb;21(2):158-60
9988264
J Exp Med. 1996 Mar 1;183(3):721-4
8642275
Ann N Y Acad Sci. 2006 Oct;1079:9-18
17130526
J Exp Med. 2005 Apr 18;201(8):1333-46
15837817
J Immunol. 2003 Oct 1;171(7):3348-52
14500627
Cell. 2006 Jul 28;126(2):375-87
16873067
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9166-71
16757567
J Immunol. 2002 Apr 15;168(8):4192-201
11937580
Annu Rev Med. 1998;49:391-405
9509271
Cytokine. 1999 Dec;11(12):1065-75
10623432
Cytokine Growth Factor Rev. 2006 Oct;17(5):349-66
16911870
Nat Immunol. 2003 Apr;4(4):337-42
12612581
Eur J Immunol. 2007 Jul;37(7):1764-72
17523134
J Immunol. 1993 Feb 1;150(3):960-70
8380826
Science. 2003 Feb 14;299(5609):1057-61
12522256
Nat Genet. 2001 Jan;27(1):20-1
11137993
Annu Rev Immunol. 2008;26:453-79
18062768
J Exp Med. 1996 Feb 1;183(2):631-7
8627174
Diabetes. 2004 Jul;53(7):1884-9
15220214
J Exp Med. 2003 Jul 21;198(2):249-58
12874258
J Leukoc Biol. 2006 Sep;80(3):458-70
16809644
J Exp Med. 2005 Nov 21;202(10):1387-97
16301745
Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8886-91
12857946
Diabetes. 2005 May;54(5):1407-14
15855327
Cytokine. 2002 Jan 21;17(2):82-90
11886175
Nature. 2003 May 29;423(6939):506-11
12724780
Immunol Rev. 2006 Aug;212:8-27
16903903
Blood. 1995 Aug 1;86(3):1170-6
7620170
Cytokine Growth Factor Rev. 2002 Feb;13(1):27-40
11750878
J Immunol. 2004 Apr 15;172(8):4691-9
15067044
Nat Genet. 2007 Sep;39(9):1074-82
17676041
Nature. 2006 Jun 15;441(7095):890-3
16778891
J Exp Med. 1995 Dec 1;182(6):1769-76
7500021
Nat Rev Immunol. 2002 Jun;2(6):389-400
12093005
J Immunol. 2007 Jan 1;178(1):242-52
17182561
J Immunol. 2002 Dec 1;169(11):6210-7
12444126
Trends Biochem Sci. 2006 Feb;31(2):89-97
16403636
Nat Immunol. 2003 Apr;4(4):330-6
12612578
J Immunol. 1994 Apr 1;152(7):3630-6
8144938
Ann Intern Med. 1990 Oct 15;113(8):619-27
2205142
Am J Hum Genet. 2007 Dec;81(6):1284-8
17999365
Nat Genet. 2007 Mar;39(3):329-37
17277778
J Exp Med. 1990 Jul 1;172(1):159-67
2162904
Nat Genet. 2008 Feb;40(2):211-6
18204447
Diabetes. 2004 Aug;53(8):1972-8
15277375
Clin Endocrinol (Oxf). 2007 Apr;66(4):508-12
17371467
J Autoimmun. 2005 Feb;24(1):55-62
15725577
Immunol Today. 1996 Jul;17(7):323-9
8763818
Genes Immun. 2008 Mar;9(2):115-21
18200031
J Clin Invest. 2002 Jan;109(1):131-40
11781358
Nat Immunol. 2005 Feb;6(2):152-62
15640801
Immunity. 1995 Oct;3(4):521-30
7584142
Nature. 1991 Aug 15;352(6336):621-4
1830926
J Immunol. 2007 Apr 1;178(7):4062-71
17371960
J Leukoc Biol. 2008 Aug;84(2):460-7
18467656
J Autoimmun. 2005;25 Suppl:29-33
16257508
J Exp Med. 2005 Mar 7;201(5):723-35
15753206
Eur J Immunol. 2005 Apr;35(4):1193-200
15770696
Semin Immunol. 2006 Apr;18(2):89-92
16473523
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3168-71
9096364
Gut. 2001 Nov;49(5):636-43
11600465
Diabetes. 2008 Jan;57(1):113-23
17928397
J Immunol. 1982 Aug;129(2):469-74
6806371
J Immunol. 2006 Nov 15;177(10):7303-11
17082649
J Exp Med. 2004 Jun 7;199(11):1479-89
15184501
J Immunol. 1987 May 15;138(10):3532-8
3033076
J Immunol. 2000 Apr 1;164(7):3527-34
10725707
J Exp Med. 2003 Sep 1;198(5):737-46
12939344
Nat Genet. 2001 Jan;27(1):18-20
11137992
J Exp Med. 2007 Mar 19;204(3):547-57
17312008
J Biol Chem. 1996 Sep 20;271(38):23055-60
8798495
Nat Rev Immunol. 2004 Sep;4(9):665-74
15343366
Adv Immunol. 1998;70:1-81
9755337
J Immunol. 1993 Mar 1;150(5):1979-87
8436829
Nature. 2007 Apr 5;446(7136):685-9
17377532
J Autoimmun. 1999 Sep;13(2):247-55
10479393
Nature. 1994 Sep 8;371(6493):130-6
8072542
Lancet. 2001 Jul 21;358(9277):221-9
11476858
J Clin Invest. 2000 Dec;106(12):R75-81
11120765
Am J Hum Genet. 2004 Aug;75(2):330-7
15208781
J Exp Med. 2007 Jan 22;204(1):65-71
17227909
Eur J Immunol. 2007 Jun;37(6):1502-12
17492805
Diabetes. 2005 Jan;54(1):92-9
15616015
J Immunol. 2005 Aug 1;175(3):1677-85
16034108
Immunity. 2000 Apr;12(4):431-40
10795741
Int Immunol. 2005 Aug;17(8):1009-21
15980098
Proc Natl Acad Sci U S A. 1985 Sep;82(18):6281-5
3929255
Hum Hered. 2003;56(1-3):18-31
14614235
J Allergy Clin Immunol. 2007 Feb;119(2):482-7
17196245
Immunology. 1989 May;67(1):44-50
2661416
Diabetes. 2005 May;54(5):1415-22
15855328
Science. 2005 Nov 18;310(5751):1159-63
16293754
J Immunol. 2003 Oct 15;171(8):4040-7
14530324
Immunity. 2008 May;28(5):687-97
18468463
J Immunol. 1998 Nov 15;161(10):5430-7
9820518
Curr Opin Rheumatol. 2003 Jul;15(4):430-5
12819471
Immunol Lett. 1988 Dec;19(4):299-307
2977379
Nature. 2007 Jun 7;447(7145):661-78
17554300
J Exp Med. 1990 May 1;171(5):1821-6
2110244
Diabetologia. 2002 Jan;45(1):21-35
11845220
J Immunol. 1985 Nov;135(5):3172-7
3930598
Nature. 1984 Oct 18-24;311(5987):626-31
6090948
J Biol Chem. 1996 May 3;271(18):10453-60
8631840
J Immunol. 2001 Feb 1;166(3):1675-83
11160210
Eur J Immunol. 2005 Jun;35(6):1681-91
15902688
J Immunol. 1984 Aug;133(2):779-83
6203980
Annu Rev Immunol. 1993;11:245-68
8476561
Cytokine. 2000 May;12(5):477-82
10857762
J Exp Med. 2004 Aug 2;200(3):287-95
15289500
Scand J Immunol. 2002 Jun;55(6):546-59
12028557
J Biol Chem. 1996 May 3;271(18):10738-44
8631883
N Engl J Med. 2007 Aug 30;357(9):851-62
17660530
J Immunol. 2008 May 1;180(9):5789-93
18424696
EMBO J. 1986 Dec 1;5(12):3275-80
3102228
J Immunol. 1986 Jun 1;136(11):4099-105
3084654
Blood. 2005 Jan 15;105(2):697-702
15353479
Proc Natl Acad Sci U S A. 1981 Apr;78(4):2517-21
6787609
Biol Signals Recept. 1998 May-Jun;7(3):148-56
9672758
Nat Genet. 2001 Oct;29(2):233-7
11586306
J Immunol. 1986 Dec 15;137(12):3845-54
3491151
J Immunol. 1995 Aug 1;155(3):1151-64
7636184
Nature. 1981 May 28;291(5813):335-8
6164929
Proc Natl Acad Sci U S A. 1990 Oct;87(19):7698-702
2145580
Diabetes. 2004 Nov;53(11):3020-3
15504986
Nat Immunol. 2001 Sep;2(9):882-8
11526406
Annu Rev Immunol. 1995;13:179-200
7612220
J Immunol. 2001 Aug 1;167(3):1245-53
11466340
Diabetes. 2007 Mar;56(3):604-12
17327427
Blood. 2006 Apr 1;107(7):2797-805
16357323
Nat Immunol. 2005 Nov;6(11):1142-51
16227984
Diabetes. 2005 Jan;54(1):107-15
15616017
Nat Biotechnol. 2004 Aug;22(8):1013-6
15235610
Cell. 1993 Oct 22;75(2):253-61
8402910
Genome Res. 2000 Apr;10(4):446-53
10779485
Annu Rev Immunol. 2004;22:531-62
15032588
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10878-83
12949259
Immunology. 1992 Feb;75(2):299-304
1551692
Eur J Immunol. 1994 Feb;24(2):440-4
7507846
Nat Genet. 2004 Apr;36(4):337-8
15004560
Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6777-82
11390999
Nat Genet. 2007 Jul;39(7):827-9
17558408
Immunology. 1997 May;91(1):28-34
9203962
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2788-93
16477002
J Mol Biol. 1991 Jun 20;219(4):717-25
1829116
J Exp Med. 1984 Nov 1;160(5):1597-602
6092512
Nat Genet. 2007 Jul;39(7):857-64
17554260
Diabetes. 2007 Apr;56(4):1174-6
17395754
Immunol Cell Biol. 2007 Jun;85(4):338-42
17372610
J Clin Invest. 2006 Sep;116(9):2423-33
16955142
J Immunol. 2004 Oct 15;173(8):4994-5001
15470042
Am J Hum Genet. 2005 May;76(5):773-9
15776395
Science. 2005 Jun 3;308(5727):1477-80
15933202
J Biol Chem. 1990 Nov 25;265(33):20252-8
2243089
Arthritis Rheum. 2002 May;46(5):1390-8
12115247
Proc Natl Acad Sci U S A. 1980 Oct;77(10):6134-8
6969402
J Immunol. 1987 Aug 1;139(3):855-62
3036946