Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells
Jingsong Wang, … , David M. Dorfman, Laurie H. Glimcher
Jingsong Wang, … , David M. Dorfman, Laurie H. Glimcher
Published February 1, 2006
Citation Information: J Clin Invest. 2006;116(2):414-421. https://doi.org/10.1172/JCI26631.
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Research Article Immunology

Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells

Abstract

The transcription factor T-bet (Tbx21) plays a major role in adaptive immunity and is required for optimal IFN-γ production by DCs. Here we demonstrate an essential function for T-bet in DCs in controlling inflammatory arthritis. We show that collagen antibody–induced arthritis (CAIA), a model of human RA, is a bipartite disease characterized by an early innate immune system component intact in RAG2–/– mice and a later adaptive immune system phase. Mice lacking T-bet had markedly reduced joint inflammation at both early and late time points and RAG2–/–T-bet–/– double-deficient mice were essentially resistant to disease. Remarkably, adoptive transfer of T-bet–expressing DCs reconstituted inflammation in a T-bet deficient and T-bet/RAG2–deficient milieu. T-bet regulates the production of proinflammatory cytokine IL-1α and chemokines macrophage inflammatory protein-1α (MIP-1α) and thymus- and activation-related chemokine (TARC) by DCs. Further, T-bet expression in DCs is required for T helper cell activation. We conclude that T-bet plays a vital function in DCs that links innate and adaptive immunity to regulate inflammatory responses. T-bet provides an attractive new target for the development of novel therapeutics for inflammatory arthritis.

Authors

Jingsong Wang, John W. Fathman, Geanncarlo Lugo-Villarino, Lucila Scimone, Ulrich von Andrian, David M. Dorfman, Laurie H. Glimcher

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Figure 4

Adoptive transfer of WT but not T-bet KO DCs restores inflammatory arthritis.

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Adoptive transfer of WT but not T-bet KO DCs restores inflammatory arthr...
Clinical signs of inflammation were scored and plotted at different time points as indicated. Individual cell components of the innate immune system were evaluated for their role in the development of arthritis. (A) RAG2–/– on C57BL/6 background (B6 RAG2 KO) and the same strain of mice depleted of NK cells in vivo by repeated injection of anti-NK1.1 (anti-NK1.1). (B) T-bet KO mice and (C) RAG2–/–T-bet–/– DKO mice received 0.3 × 106 purified WT or T-bet KO splenic DCs. Unpaired Student’s t tests were performed on days 6 and 12 after arthritis induction. *P > 0.5; **P > 0.3; #P < 0.02; ##P < 0.001; †P < 0.003; ††P > 0.2.