Defective CD4+CD25+ regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-gamma.
Mice with a deficiency in IFN-gamma or IFN-gamma receptor (IFN-gammaR) are more susceptible to collagen-induced arthritis (CIA), an experimental autoimmune disease that relies on the use of complete Freund's adjuvant (CFA). Here we report that the heightened susceptibility of IFN-gammaR knock-out (KO) mice is associated with a functional impairment of CD4+CD25+ Treg cells. Treatment of wild-type mice with depleting anti-CD25 antibody after CFA-assisted immunisation with collagen type II (CII) significantly accelerated the onset of arthritis and increased the severity of CIA. This is an indication of a role of Treg cells in the effector phase of CIA. IFN-gammaR deficiency did not affect the number of CD4+CD25+ T cells in the central and peripheral lymphoid tissues. In addition, CD4+CD25+ T cells isolated from naive IFN-gammaR KO mice had a normal potential to suppress T cell proliferation in vitro. However, after immunisation with CII in CFA, the suppressive activity of CD4+CD25+ T cells became significantly more impaired in IFN-gammaR-deficient mice. Moreover, expression of the mRNA for Foxp3, a highly specific marker for Treg cells, was lower. We further demonstrated that the effect of endogenous IFN-gamma, which accounts for more suppressive activity in wild-type mice, concerns both Treg cells and accessory cells. Our results demonstrate that the decrease in Treg cell activity in CIA is counter-regulated by endogenous IFN-gamma.
Kelchtermans
Hilde
H
Laboratory of Immunobiology, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium. hilde.kelchtermans@rega.kuleuven.ac.be
De Klerck
Bert
B
Mitera
Tania
T
Van Balen
Maarten
M
Bullens
Dominique
D
Billiau
Alfons
A
Leclercq
Georges
G
Matthys
Patrick
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018920:Coculture Techniques; D024043:Collagen Type II / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D007114:Immunization; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D024043:Collagen Type II; D005620:Freund's Adjuvant; D007371:Interferon-gamma; D017471:Receptors, Interferon; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; D000096743:Interferon gamma Receptor
Arthritis Rheum. 2001 Oct;44(10):2413-24
11665984
J Immunol. 1997 Jun 1;158(11):5501-6
9164973
Science. 2003 Feb 14;299(5609):1033-6
12532024
Arthritis Rheum. 1986 Jan;29(1):106-13
3947407
Nat Immunol. 2003 Apr;4(4):330-6
12612578
J Exp Med. 1985 Sep 1;162(3):1105-10
3928802
J Immunol. 1998 Feb 1;160(3):1212-8
9570536
Curr Opin Immunol. 2001 Dec;13(6):644-9
11677084
Arthritis Res Ther. 2004;6(1):19-25
14979928
J Immunol. 2003 Nov 15;171(10):5012-7
14607897
J Immunol. 2004 Jan 15;172(2):834-42
14707053
Arthritis Res Ther. 2004;6(3):R220-31
15142268
Methods. 2001 Dec;25(4):386-401
11846608
Immunology. 2001 Jul;103(3):291-300
11454058
Int Immunol. 1998 Dec;10(12):1969-80
9885918
Eur J Immunol. 1996 Jul;26(7):1608-12
8766568
J Immunol. 1997 Jun 1;158(11):5507-13
9164974
J Immunol. 2002 Nov 1;169(9):4712-6
12391178
J Exp Med. 1998 Jul 20;188(2):287-96
9670041
Adv Immunol. 1996;62:61-130
8781267
Arthritis Rheum. 1986 Dec;29(12):1501-9
3801072
J Immunol. 1999 May 1;162(9):5317-26
10228007
Eur J Immunol. 2000 Jun;30(6):1538-43
10898488
J Exp Med. 2004 Jun 21;199(12):1619-30
15210741
Trends Immunol. 2001 Jul;22(7):367-71
11429320
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15059-64
14608036
J Exp Med. 1987 Oct 1;166(4):1055-69
3116143
Springer Semin Immunopathol. 2003 Aug;25(1):3-18
12904888
J Immunol. 1999 Sep 15;163(6):3503-10
10477624
Gene. 2002 Feb 20;285(1-2):1-24
12039028
Nat Immunol. 2001 Apr;2(4):301-6
11276200
J Exp Med. 2004 Jan 5;199(1):25-34
14699080
J Biol Chem. 1998 Jan 2;273(1):309-14
9417081
Adv Immunol. 1998;70:1-81
9755337
Eur J Immunol. 2004 Mar;34(3):623-630
14991591
J Leukoc Biol. 2001 Dec;70(6):849-60
11739546
Nat Immunol. 2001 Sep;2(9):816-22
11526392
Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8213-8
12034883
Arthritis Res Ther. 2004;6(3):R213-9
15142267
Cytokine Growth Factor Rev. 2003 Apr;14(2):85-9
12651220
Arthritis Rheum. 2003 May;48(5):1452-60
12746920
Science. 1993 Mar 19;259(5102):1742-5
8456301
J Exp Med. 2003 Dec 15;198(12):1875-86
14676299
J Immunol. 1995 Aug 1;155(3):1151-64
7636184
Ann Rheum Dis. 2003 Oct;62(10):983-90
12972478
Arthritis Res Ther. 2003;5(2):R106-13
12718754
J Exp Med. 2001 Sep 3;194(5):629-44
11535631
Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374-8
2950524
Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10878-83
12949259