title: T-bet as a key regulator of mucosal immunity.
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.
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, King's College London, London, UK.|National Institute for Health Research Biomedical Research Centre, Guy's and St Thomas' National Health Service Foundation Trust, London, UK.|The Francis Crick Institute, Mill Hill Laboratory, The Ridgeway Mill Hill, London NW7 1AA, UK.
authors.forename: Rami
authors.initials: R
authors.lastname: Mohamed
authors.affiliation: Division of Transplantation Immunology and Mucosal Biology, Department of Experimental Immunobiology, King's College London, London, UK.
authors.forename: Graham M
authors.initials: GM
authors.lastname: Lord
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D055808:Drug Discovery; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal; D056747:Immunomodulation; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
keywords: T-bet; TBX21; mucosal homeostasis; mucosal immunity