title: Defective CD4+CD25+ regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-gamma.
abstract: 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.
authors.affiliation: Laboratory of Immunobiology, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium. hilde.kelchtermans@rega.kuleuven.ac.be
authors.forename: Hilde
authors.initials: H
authors.lastname: Kelchtermans
authors.forename: Bert
authors.initials: B
authors.lastname: De Klerck
authors.forename: Tania
authors.initials: T
authors.lastname: Mitera
authors.forename: Maarten
authors.initials: M
authors.lastname: Van Balen
authors.forename: Dominique
authors.initials: D
authors.lastname: Bullens
authors.forename: Alfons
authors.initials: A
authors.lastname: Billiau
authors.forename: Georges
authors.initials: G
authors.lastname: Leclercq
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
mesh_terms: 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
chemical_list: 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
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