The transcription factor T-bet regulates mucosal T cell activation in experimental colitis and Crohn's disease.
The balance between pro and antiinflammatory cytokines secreted by T cells regulates both the initiation and perpetuation of inflammatory bowel diseases (IBD). In particular, the balance between interferon (IFN)-gamma/interleukin (IL)-4 and transforming growth factor (TGF)-beta activity controls chronic intestinal inflammation. However, the molecular pathways that evoke these responses are not well understood. Here, we describe a critical role for the transcription factor T-bet in controlling the mucosal cytokine balance and clinical disease. We studied the expression and function of T-bet in patients with IBD and in mucosal T cells in various T helper (Th)1- and Th2-mediated animal models of chronic intestinal inflammation by taking advantage of mice that lack T-bet and retroviral transduction techniques, respectively. Whereas retroviral transduction of T-bet in CD62L(+) CD4(+) T cells exacerbated colitis in reconstituted SCID mice, T-bet-deficient T cells failed to induce colitis in adoptive transfer experiments suggesting that overexpression of T-bet is essential and sufficient to promote Th1-mediated colitis in vivo. Furthermore, T-bet-deficient CD62L(-) CD4(+) T cells showed enhanced protective functions in Th1-mediated colitis and exhibited increased TGF-beta signaling suggesting that a T-bet driven pathway of T cell activation controls the intestinal balance between IFN-gamma/IL-4 and TGF-beta responses and the development of chronic intestinal inflammation in T cell-mediated colitis. Furthermore, TGF-beta was found to suppress T-bet expression suggesting a reciprocal relationship between TGF-beta and T-bet in mucosal T cells. In summary, our data suggest a key regulatory role of T-bet in the pathogenesis of T cell-mediated colitis. Specific targeting of this pathway may be a promising novel approach for the treatment of patients with Crohn's disease and other autoimmune diseases mediated by Th1 T lymphocytes.
Neurath
M F
MF
Laboratory of Immunology, I. Medical Clinic, University of Mainz, 55131 Mainz, Germany. neurath@1-med.klinik.uni-mainz.de
Weigmann
B
B
Finotto
S
S
Glickman
J
J
Nieuwenhuis
E
E
Iijima
H
H
Mizoguchi
A
A
Mizoguchi
E
E
Mudter
J
J
Galle
P R
PR
Bhan
A
A
Autschbach
F
F
Sullivan
B M
BM
Szabo
S J
SJ
Glimcher
L H
LH
Blumberg
R S
RS
D000328:Adult; D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003092:Colitis / Q000276:immunology*; D003424:Crohn Disease / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D018014:Gene Transfer Techniques; D016654:Genes, RAG-1; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018928:Immunity, Mucosal; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D020825:T-Box Domain Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D000098815:T-bet Transcription Factor
D016207:Cytokines; D017931:DNA Primers; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; C064658:RAG-1 protein