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Open Access Research article

IL-10 signaling in CD4+ T cells is critical for the pathogenesis of collagen-induced arthritis

Jian Tao1, Masahito Kamanaka2, Jianlei Hao3, Zhifang Hao4, Xi Jiang5, Joe E Craft1, Richard A Flavell2, Zhenzhou Wu3, Zhangyong Hong3, Liqing Zhao3 and Zhinan Yin13*

Author Affiliations

1 Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520-8031, USA

2 Department of Immunobiology, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06520-8031, USA

3 College of Life Sciences, Nankai University, 94 Weijin Road, Tianjin, 300071, China

4 Department of Surgery, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA

5 Department of Reconstructive Sciences, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA

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Arthritis Research & Therapy 2011, 13:R212  doi:10.1186/ar3545

Published: 22 December 2011

Abstract

Introduction

IL-10 is a very important anti-inflammatory cytokine. However, the role of this cytokine in T cells in the pathogenesis of collagen-induced arthritis is unclear. The purpose of this study was to define the role of IL-10 signaling in T cells in the pathogenesis of collagen-induced arthritis.

Methods

IL-10 receptor dominant-negative transgenic (Tg) and control mice were immunized with bovine type II collagen to induce arthritis. The severity of arthritis was monitored and examined histologically. T-cell activation and cytokine production were analyzed using flow cytometry. T-cell proliferation was examined by [3H]thymidine incorporation. Antigen-specific antibodies in serum were measured by ELISA. Foxp3 expression in CD4+ regulatory T cells (Tregs) was determined by intracellular staining or Foxp3-RFP reporter mice. The suppressive function of Foxp3+CD4+ Tregs was determined in vitro by performing a T-cell proliferation assay. The level of IL-17 mRNA in joints was measured by real-time PCR. A two-tailed nonparametric paired test (Wilcoxon signed-rank test) was used to calculate the arthritis and histological scores. Student's paired or unpaired t-test was used for all other statistical analyses (InStat version 2.03 software; GraphPad Software, San Diego, CA, USA).

Results

Blocking IL-10 signaling in T cells rendered mice, especially female mice, highly susceptible to collagen-induced arthritis. T-cell activation and proliferation were enhanced and produced more IFN-γ. The suppressive function of CD4+Foxp3+ regulatory T cells was significantly impaired in Tg mice because of the reduced ability of Tregs from Tg mice to maintain their levels of Foxp3. This was further confirmed by transferring Foxp3-RFP cells from Tg or wild-type (Wt) mice into a congenic Wt host. The higher level of IL-17 mRNA was detected in inflammatory joints of Tg mice, probably due to the recruitment of IL-17+γδ T cells into the arthritic joints.

Conclusion

IL-10 signaling in T cells is critical for dampening the pathogenesis of collagen-induced arthritis by maintaining the function of Tregs and the recruitment of IL-17+γδ T cells.