title: Overexpression of T-bet gene regulates murine autoimmune arthritis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan.
authors: Yuya
authors: Y
authors: Kondo
authors: Mana
authors: M
authors: Iizuka
authors: Ei
authors: E
authors: Wakamatsu
authors: Zhaojin
authors: Z
authors: Yao
authors: Masahiro
authors: M
authors: Tahara
authors: Hiroto
authors: H
authors: Tsuboi
authors: Makoto
authors: M
authors: Sugihara
authors: Taichi
authors: T
authors: Hayashi
authors: Keigyou
authors: K
authors: Yoh
authors: Satoru
authors: S
authors: Takahashi
authors: Isao
authors: I
authors: Matsumoto
authors: Takayuki
authors: T
authors: Sumida
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D013264:Stifle / Q000473:pathology; D013583:Synovial Membrane / Q000473:pathology; D020825:T-Box Domain Proteins / Q000235:genetics* / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma