T-bet and mucosal Th1 responses in the gastrointestinal tract

Abstract

T cells play an essential role in regulating mucosal immune responses in the gastrointestinal tract. Recent observations on T helper cell differentiation and activation by regulatory transcription factors-especially T-bet-in chronic inflammatory diseases have provided new perspectives for understanding mucosal immunity. Here we summarise recent advances in the field of transcription factors and discuss the implications of these findings for future therapeutic approaches in inflammatory bowel diseases. In particular, we have focused on the role of T-bet in controlling mucosal Th1 responses in the gastrointestinal tract.

Figure 1

Transcriptional control of T cell differentiation.³² The cytokines interleukin (IL)-4 and IL-12 direct the development of Th2 and Th1 cells from naïve CD4⁺ T cells. Antigen presenting cells (APCs), such as dendritic cells and macrophages, produce cytokines such as IL-6, tumour necrosis factor (TNF), interferon γ (IFN-γ), IL-12, and IL-18 after activation. IL-12, IFN-γ, and IL-18 bind to their specific receptors on the surface of the differentiating Th1 cell. Signalling via the IL-12 receptor induces activation of the transcription factor STAT-4 whereas IFN-γ signalling leads to activation of STAT-1 and the transcription factor T-bet. T-bet induces IFN-γ production and expression of the high affinity IL-12 receptor on T cells. IL-18 alone cannot induce Th1 cell differentiation but augments IL-12 induced Th1 T cell development. TNF and IL-6 have costimulatory effects on Th1 cells. In Th2 T cell differentiation, the IL-4 inducible transcription factor STAT-6 activates GATA-3 leading to production of IL-4, IL-5, and IL-13. Furthermore, the transcription factor c-maf induces IL-4 gene expression.