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

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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