Overexpression of T‐bet gene regulates murine autoimmune arthritis
Copyright policy )Overexpression of T‐bet gene regulates murine autoimmune arthritis
AbstractObjectiveTo clarify the role of T‐bet in the pathogenesis of collagen‐induced arthritis (CIA).MethodsT‐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.ResultsUnlike 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.ConclusionOverexpression 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.
- University of Tsukuba Japan
- Harvard University United States
CD4-Positive T-Lymphocytes, Male, Mice, Knockout, Interleukin-17, Gene Expression, Autoimmunity, Dendritic Cells, Nuclear Receptor Subfamily 1, Group F, Member 3, Arthritis, Experimental, Stifle, Coculture Techniques, Arthritis, Rheumatoid, Mice, Inbred C57BL, Interferon-gamma, Mice, Animals, Female, Lymph Nodes, Lymphocytes, Cells, Cultured
CD4-Positive T-Lymphocytes, Male, Mice, Knockout, Interleukin-17, Gene Expression, Autoimmunity, Dendritic Cells, Nuclear Receptor Subfamily 1, Group F, Member 3, Arthritis, Experimental, Stifle, Coculture Techniques, Arthritis, Rheumatoid, Mice, Inbred C57BL, Interferon-gamma, Mice, Animals, Female, Lymph Nodes, Lymphocytes, Cells, Cultured
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