Abstract
Initially understood to be a key regulator of interferon-γ-producing helper T cells, our knowledge of T-bet's functional roles has expanded to encompass a growing range of cellular lineages. In addition to regulating other interferon-γ-producing adaptive immune cells, it is now clear that T-bet plays a fundamental role in the regulation of innate immune responses across mucosal surfaces. This homeostatic role is demonstrated by the spontaneous colitis that occurs when T-bet is deleted from innate immune cells in RAG(-/-) mice. Using this model as a focal point, we review our understanding of T-bet's regulation of adaptive and innate immune systems, focusing particularly on mucosal populations including innate lymphoid cells, dendritic cells and intraepithelial lymphocytes. With the increasingly diverse effects of T-bet on different lineages, the classical binding-centric paradigm of T-bet's molecular functionality has increasingly struggled to account for the versatility of T-bet's biological effects. Recent recognition of the synergistic interactions between T-bet and other canonical transcription factors has led to a co-operative paradigm that has provided greater explanatory power. Synthesizing insights from ChIP-seq and comparative biology, we expand the co-operative paradigm further and suggest a network approach as a powerful way to understand and model T-bet's diverse functionality.