Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 116, Issue 2, Pages 414-421Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI26631
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Funding
- NIAID NIH HHS [AI56296, K08 AI57434, P01 AI056296, K08 AI057434] Funding Source: Medline
- NIAMS NIH HHS [AR46983, R01 AR046983] Funding Source: Medline
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The transcription factor T-bet (Thx21) plays a major role in adaptive immunity and is required for optimal IFN-gamma 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-1 alpha and chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha) 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.
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