GM-CSF mediates autoimmunity by enhancing IL-6-dependent Th17 cell development and survival.
Granulocyte macrophage-colony stimulating factor (GM-CSF) is critically involved in development of organ-related autoimmune inflammatory diseases including experimental allergic encephalitis and collagen-induced arthritis. Roles of GM-CSF in the initiation and in the effector phase of the autoimmune response have been proposed. Our study was designed to investigate the mechanisms of GM-CSF in autoimmunity using a model of autoimmune heart inflammatory disease (myocarditis). The pathological sequel after immunization with heart myosin has been shown previously to depend on IL-1, IL-6, IL-23, and IL-17. We found that innate GM-CSF was critical for IL-6 and IL-23 responses by dendritic cells and generation of pathological Th17 cells in vivo. Moreover, GM-CSF promoted autoimmunity by enhancing IL-6-dependent survival of antigen specific CD4(+) T cells. These results suggest a novel role for GM-CSF in promoting generation and maintenance of Th17 cells by regulation of IL-6 and IL-23 in vivo.
Sonderegger
Ivo
I
Institute of Integrative Biology, Molecular Biomedicine, ETH Zürich, 8952 Zürich, Switzerland.
Iezzi
Giandomenica
G
Maier
Reinhard
R
Schmitz
Nicole
N
Kurrer
Michael
M
Kopf
Manfred
M
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009205:Myocarditis / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
J Exp Med. 2006 Aug 7;203(8):2009-19
16880257
J Immunol. 1993 Nov 15;151(10):5145-53
7693805
J Immunol. 1991 Oct 1;147(7):2141-7
1918949
Nature. 2006 May 11;441(7090):231-4
16648837
J Immunol. 1987 Aug 15;139(4):1113-9
3038997
Trends Immunol. 2002 Aug;23(8):403-8
12133803
Blood. 1991 Mar 15;77(6):1131-45
2001448
Nature. 2007 Jul 26;448(7152):484-487
17581588
Autoimmunity. 2002 Mar;35(2):97-104
12071442
J Immunol. 2001 Nov 1;167(9):5464-9
11673566
Circulation. 2001 Dec 18;104(25):3145-51
11748115
Nat Med. 2003 Dec;9(12):1484-90
14625544
Nature. 2006 May 11;441(7090):235-8
16648838
Immunity. 2006 Feb;24(2):179-89
16473830
J Immunol. 1998 Oct 1;161(7):3639-44
9759887
Eur J Immunol. 2000 Jul;30(7):2056-64
10940895
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8222-6
9653168
Nature. 1998 Mar 19;392(6673):245-52
9521319
J Immunol Methods. 2004 Dec;295(1-2):79-87
15627613
J Exp Med. 2003 Feb 3;197(3):323-31
12566416
Immunity. 2006 Aug;25(2):309-18
16919486
J Immunol. 2000 May 1;164(9):4878-82
10779797
J Clin Invest. 2006 May;116(5):1310-6
16670770
Nat Immunol. 2005 Nov;6(11):1133-41
16200068
Eur J Immunol. 2006 Nov;36(11):2849-56
17039570
J Exp Med. 2001 Oct 1;194(7):873-82
11581310
Science. 2003 Feb 14;299(5609):1033-6
12532024
J Exp Med. 2005 Jan 17;201(2):233-40
15657292
Nat Immunol. 2006 Sep;7(9):929-36
16906167
J Immunol. 2007 Jan 1;178(1):39-48
17182538
J Exp Med. 1992 Dec 1;176(6):1693-702
1460426
Immunity. 2003 Jul;19(1):71-82
12871640
Science. 1990 Dec 21;250(4988):1720-3
2125367
Neurosci Lett. 2002 Nov 8;332(3):185-9
12399011
Arthritis Res. 2001;3(5):293-8
11549370
J Immunol. 1998 Dec 15;161(12):6480-6
9862671
Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5592-6
8202532
Nature. 2003 Feb 13;421(6924):744-8
12610626
J Exp Med. 2006 Jul 10;203(7):1685-91
16818675
Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12557-61
9356488
J Exp Med. 2003 Dec 15;198(12):1951-7
14662908
J Immunol. 2005 Apr 15;174(8):4761-7
15814701
Eur J Immunol. 1998 Jul;28(7):2178-87
9692887
J Immunol. 2006 Jul 1;177(1):566-73
16785554
J Neuroimmunol. 1999 Nov 15;101(2):188-96
10580801
Arthritis Rheum. 1999 Aug;42(8):1635-43
10446862
J Immunol. 2000 Dec 1;165(11):6107-15
11086043
J Exp Med. 2002 Jan 7;195(1):15-21
11781361
J Clin Invest. 2006 May;116(5):1317-26
16670771
J Exp Med. 2006 Oct 2;203(10):2271-9
16982811
J Exp Med. 2007 Jan 22;204(1):161-70
17200411
Cell. 2001 Aug 10;106(3):255-8
11509172
J Immunol. 2003 Dec 1;171(11):6173-7
14634133
J Exp Med. 1992 May 1;175(5):1157-67
1569392
Growth Factors. 2004 Dec;22(4):225-31
15621725
Nat Med. 2000 May;6(5):583-8
10802717
Circulation. 2003 Jan 21;107(2):320-5
12538435
Cell. 2006 Sep 22;126(6):1121-33
16990136