Transcription factor T-bet regulates inflammatory arthritis through its function in dendritic cells.
The transcription factor T-bet (Tbx21) 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 RAG2T-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-1alpha and chemokines macrophage inflammatory protein-1alpha (MIP-1alpha) 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.
Wang
Jingsong
J
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Fathman
John W
JW
Lugo-Villarino
Geanncarlo
G
Scimone
Lucila
L
von Andrian
Ulrich
U
Dorfman
David M
DM
Glimcher
Laurie H
LH
D019264:Adoptive Transfer; D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D002465:Cell Movement; D018925:Chemokines / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000098815:T-bet Transcription Factor
D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors