CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4+CD25+Foxp3+ regulatory T cell population |
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Authors: | Hyeok-Jae Ko Mi-La Cho Seon-Yeong Lee Hye-Jwa Oh Yu-Jung Heo Young-Mee Moon Chang-Min Kang Seung-Ki Kwok Ji Hyeon Ju Sung-Hwan Park Kyung-Su Park Ho-Youn Kim |
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Institution: | 1. Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea;2. Convergent Research Consortium for Immunologic Disease, The Catholic University of Korea, Seoul, South Korea;3. Department of Internal Medicine, Incheon St. Mary''s Hospital, The Catholic University of Korea, Incheon, South Korea;4. Division of Rheumatology, Department of Internal Medicine, Hallym University, Seoul, South Korea;5. Division of Endocrinology and Metabolism, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea |
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Abstract: | Cytotoxic T lymphocyte antigen-4 (CTLA4) and IgG fusion protein, CTLA4-Ig, is a therapeutic agent used for rheumatoid arthritis. It binds B7 molecules on dendritic cells (DCs) and thereby blocks B7/CD28 costimulatory interaction and inhibits effective T cell proliferation. However, the effect of CTLA4-Ig on the regulatory T cell (Treg) is still not known. In this study, we investigated the influence of CTLA4-Ig on the CD4+CD25+Foxp3+ Treg population in collagen-induced arthritis (CIA) mouse model. CTLA4-Ig suppressed CIA and increased the CD4+CD25+Foxp3+ Treg population in joint and spleen. When CD11c + DCs and CD4+T cells from CIA mice were cultured with anti-CD3, CTLA4-Ig increased the CD4+CD25 + Foxp3+ Treg population in a TGF-β-dependent manner. When CD11c + DCs from CIA mice were treated with CTLA4-Ig and adoptively transferred into CIA-induced mice, arthritis did not develop in association with the increase in CD4+CD25+Foxp3+ Treg population. However, in CTLA4-Ig-untreated DC-transferred CIA mice, arthritis developed and then rapidly progressed. Our study demonstrated that CTLA4-Ig suppressed CIA by modifying DCs from CIA mice into tolerogenic DCs to increase the CD4+CD25+Foxp3+ Treg population and this seems to be the new immune regulatory mechanism of CTLA4-Ig. |
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