Open AccessOverexpression of T‐bet gene regulates murine autoimmune arthritis
Author(s) -
Kondo Yuya,
Iizuka Mana,
Wakamatsu Ei,
Yao Zhaojin,
Tahara Masahiro,
Tsuboi Hiroto,
Sugihara Makoto,
Hayashi Taichi,
Yoh Keigyou,
Takahashi Satoru,
Matsumoto Isao,
Sumida Takayuki
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.33335
Subject(s) - rar related orphan receptor gamma , cd11c , microbiology and biotechnology , t cell , interleukin 17 , chemistry , biology , immunology , cytokine , immune system , biochemistry , foxp3 , gene , phenotype
Objective To clarify the role of T‐bet in the pathogenesis of collagen‐induced arthritis (CIA). Methods T‐bet–transgenic (Tg) mice under the control of the CD2 promoter were generated. CIA was induced in T‐bet–Tg mice and wild‐type C57BL/6 (B6) mice. Levels of type II collagen (CII)–reactive T‐bet and retinoic acid receptor–related orphan nuclear receptor γt (RORγt) messenger RNA expression were analyzed by real‐time polymerase chain reaction. Criss‐cross experiments using CD4+ T cells from B6 and T‐bet–Tg mice, as well as CD11c+ splenic dendritic cells (DCs) from B6 and T‐bet–Tg mice with CII were performed, and interleukin‐17 (IL‐17) and interferon‐γ (IFNγ) in the supernatants were measured by enzyme‐linked immunosorbent assay. CD4+ T cells from B6, T‐bet–Tg, or T‐bet–Tg/IFNγ −/− mice were cultured for Th17 cell differentiation, then the proportions of cells producing IFNγ and IL‐17 were analyzed by fluorescence‐activated cell sorting. Results Unlike the B6 mice, the T‐bet–Tg mice did not develop CIA. T‐bet–Tg mice showed overexpression of Tbx21 and down‐regulation of Rorc in CII‐reactive T cells. Criss‐cross experiments with CD4+ T cells and splenic DCs showed a significant reduction in IL‐17 production by CII‐reactive CD4+ T cells in T‐bet–Tg mice, even upon coculture with DCs from B6 mice, indicating dysfunction of IL‐17–producing CD4+ T cells. Inhibition of Th17 cell differentiation under an in vitro condition favoring Th17 cell differentiation was observed in both T‐bet–Tg mice and T‐bet–Tg/IFNγ −/− mice. Conclusion Overexpression of T‐bet in T cells suppressed the development of autoimmune arthritis. The regulatory mechanism of arthritis might involve dysfunction of CII‐reactive Th17 cell differentiation by overexpression of T‐bet via IFNγ‐independent pathways.