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.
