Understanding the regulation of IL-17 producing lymphocytes by the cytokine TGF (beta).

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Th17 cells are a lineage of CD4+T-helper cells that have been shown to be critical mediators of immunity at barrier surfaces such as the gastrointestinal tract and skin. At these sites these T-helper cells participate in both immune surveillance and maintenance of barrier integrity and therefore mediate protection against both bacterial and fungal infections. However, Th17 cells have also been shown to promote aberrant inflammation and are key drivers of pathology in a plethora of auto-inflammatory conditions, including multiple sclerosis, rheumatoid arthritis, and periodontitis (the latter a particular focus in the lab). Understanding these positive and negative roles for Th17 cells has been the aim of much research and it is becoming increasingly clear that Th17 cells exhibit both extensive functional diversity and plasticity. Indeed, recent studies have identified gene signatures that distinguish "pathogenic" Th17 cells, which drive tissue inflammation and damage, from barrier protective "homeostatic" Th17 cells. However, the extracellular signals that drive acquisition of these disparate fates and functions of Th17 cells remain poorly understood, but would herald an important advance allowing the selective inhibition of pathogenic Th17 cells to become a therapeutic reality. The aim of this project is to mechanistically understand how Th17 cells integrate local signals to be trained to take on "homeostatic" and "pathogenic" functions. This project will employ sophisticated transgenic mouse models, alongside examination of Th17 cells from human tissue samples, to generate unprecedented insight into how Th17 cells acquire distinct functional capabilities. By operating across immunology, molecular biology, bioinformatics and translational medicine fields the student will gain vital understanding of the value of interdisciplinary approaches and be trained in cutting-edge immunology techniques including: in vivo models of inflammation, in vitro culture of immune cells, multicolour flow-cytometry, and genome-wide transcriptional profiling. Ultimately, this project aims to inform development of novel therapeutics to that will allow precise manipulation of Th17 cells. Moreover, data generated will improve our current understanding of Th17 cell biology, providing insight into the plethora of disorders in which aberrant Th17 cell function is implicated.