SSA Stem cell regulation in the adult thymus

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The thymus is a key organ of the adaptive immune system, responsible for T cell production throughout the lifespan. The organ has an intricate and highly organised architecture and cellularity, which is intimately linked to the different processes via which it produces a functional T cell repertoire. Of the different intrathymic cell-types, an array of specialized thymic epithelial cells (TEC) provides most of the functions required for T cell repertoire development. We are interested in developing stem cell-based approaches to boosting or replacing thymus function in patients. Through previous work, we identified the transcription factor, FOXN1, as a master regulator of TEC differentiation. Recently, we have shown that FOXN1 up-regulation can rejuvenate the thymus in aged animals (Bredenkamp Development 2014), and that expression of FOXN1 in a non-thymic cell-type, fibroblasts, forces these cells to change identity and become functional TEC (Bredenkamp Nature Cell Biology 2014). We call these reprogrammed cells induced TEC (iTEC). Additionally, we have identified a TEC stem cell population in the adult thymus (Ulyanchenko ...Blackburn, submitted). This project will further develop this work, by investigating how TEC stem cells are controlled in the adult organ and determining whether TEC stem cells can be generated by reprogramming. As part of this work, we will investigate transcription factor control of Foxn1 expression in TEC stem cells, and how self-renewal and differentiation of TEC stem cells is influenced by signals from other intrathymic cell types. The project will utilise a range of state-of-the-art approaches to identify and validate transcriptional control networks in TEC stem cell, including genetic analyses (e.g. analysis of conditional knockouts, gene knock-down and over-expression approaches in vivo and in vitro), high resolution microscopy, multi-parameter flow cytometry, gene expression analysis (RNAseq and RT-qPCR). All of the required approaches are available within the Blackburn lab or within CRM. The student will also benefit from training and exchange opportunities available through the EU-funded consortium ThymiStem (www.thymistem.org).