Open Access Highly Accessed Research article

Defective CD4+CD25+ regulatory T cell functioning in collagen-induced arthritis: an important factor in pathogenesis, counter-regulated by endogenous IFN-γ

Hilde Kelchtermans1*, Bert De Klerck1, Tania Mitera1, Maarten Van Balen1, Dominique Bullens2, Alfons Billiau1, Georges Leclercq3 and Patrick Matthys1

Author Affiliations

1 Laboratory of Immunobiology, Rega Institute for Medical Research, Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium

2 Laboratory for Experimental Immunology, Department of Pathophysiology, Faculty of Medicine, Katholieke Universiteit Leuven (KULeuven), Leuven, Belgium

3 Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Ghent, Belgium

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Arthritis Res Ther 2005, 7:R402-R415  doi:10.1186/ar1500

Published: 28 January 2005

Abstract

Mice with a deficiency in IFN-γ or IFN-γ receptor (IFN-γR) 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-γR 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-γR 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-γR 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-γR-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-γ, 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-γ.

Keywords:
arthritis; autoimmunity; interferon-γ; regulatory T cells