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Background: A TH1-specific transcription factor, T-box–containing protein expressed in T cells (T-bet), controls the production of both TH1 and TH2 cytokines in TH cell differentiation by means of distinct mechanisms. T-bet–deficient mice overproduce TH2 cytokines and have spontaneous airway inflammation. Objectives: We tested whether T-bet overexpression could protect against the development or progression of asthma. Methods: We generated a T cell–specific and inducible line of T-bet–transgenic mice on a T-bet–deficient genetic background and used it to study the function of T-bet in an ovalbumin (OVA)–induced asthma model. Results: Induction of T-bet in a T cell–specific manner in an OVA model of asthma concomitant with OVA injection prevented airway hyperresponsiveness, eosinophilic and lymphocytic inflammation, and IL-5 and IL-13 production in bronchoalveolar lavage fluid and also reduced serum IgE and TH2 cytokine production by peripheral T cells. Even when T-bet expression was induced during later stages of asthma progression, T-bet overexpression still attenuated airway hyperresponsiveness and goblet cell hyperplasia, as well as TH2 cytokine production. Conclusions: Our results suggest that T-bet expression in T cells can prevent the initiation of airway inflammation and progression of chronic inflammation and might be extrapolated to human asthma. [Copyright &y& Elsevier]

Summary: We previously described a mouse model of ulcerative colitis linked to T-bet deficiency in the innate immune system. Here, we report that the majority of T-bet −/− RAG2 −/− ulcerative colitis (TRUC) mice spontaneously progress to colonic dysplasia and rectal adenocarcinoma solely as a consequence of MyD88-independent intestinal inflammation. Dendritic cells (DCs) are necessary cellular effectors for a proinflammatory program that is carcinogenic. Whereas these malignancies arise in the setting of a complex inflammatory environment, restoration of T-bet selectively in DCs was sufficient to reduce colonic inflammation and prevent the development of neoplasia. TRUC colitis-associated colorectal cancer resembles the human disease and provides ample opportunity to probe how inflammation drives colorectal cancer development and to test preventative and therapeutic strategies preclinically. [Copyright &y& Elsevier]