T cells are vital regulators and effectors of the adaptive immune system. Production of a functional, self-tolerant T cell repertoire is a complex process that occurs in a dedicated organ, the thymus, and depends on a set of highly specialized epithelial cells that form a key part of the thymic stroma (thymic epithelial cells; TEC)(1). Two main sub-lineage of TEC exist: cortical and medullary TEC. These arise from a common progenitor/stem cell during thymus development, and are functionally distinct, regulating early T cell differentiation and central tolerance induction respectively.
In previous work, we identified the thymic epithelial progenitor/stem cells (TEPC) from which the TEC lineage first arises (2) and showed these cells can form self-organised thymic organoids in vitro (unpublished) and upon transplantation (2). Recently, we have also established that TEC can be generated in vitro by direct reprogramming of primary embryonic fibroblasts using a single transcription factor, FOXN1 (3). Like ex vivo TEPC, these ‘induced TEC’ (iTEC) can generate a thymus upon transplantation and form thymic organoids in vitro (3). Additionally, we have recently uncovered part of the mechanism controlling the very earliest development of the medullary TEC sublineage, which regulates central tolerance induction (4). We now wish to use the iTEC system to test predictive models of intrinsic and extrinsic regulation of TEPC regulation.
This interdisciplinary project is based at the interface of stem cell biology and state-of-the-art informatics analysis of transcriptome and epigenomic data. It will use a combination of bioinformatics, modelling and wet-lab approaches to predict and test regulatory networks that control the TEPC state and initiate TEC differentiation.
The successful student will receive training in stem cell biology, bioinformatics analysis of single cell and population RNAseq and ATACseq data, modelling of transcriptional networks, CAS9/CRISPR mediated genetic modification, tissue culture including of pluripotent stem cells, microdissection, cellular reaggregation techniques, thymic organoid culture, multiparameter FACS analysis, advanced imaging analysis, immunohistochemistry, RT-qPCR.
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(1) Manley, NR, Richie, ER, Blackburn, CC, Condie, B, Sage, J. (2011) Structure and function of the thymic microenvironment. Front Biosci. 17 2461-77.
(2) Bennett, A.R., Farley, A., Blair, N.F., Gordon, J., Sharp. L., and Blackburn, C.C.; (2002) Identification and characterization of thymic epithelial progenitor cells. Immunity 16 803-814
(3) Bredenkamp, N., Ulyanchenko, S., O’Neill, K.E., Manley, N.R., Vaidya, H.J. and Blackburn, C.C. (2014) An organized and functional thymus generated from FOXN1-reprogrammed fibroblasts. Nature Cell Biology, 16 902-8.
(4) Liu, D., Kousa, A.I., O’Neill, K.E., Guillemot, F., Popis, M., Farley, A.M., Tomlinson, S.R., Ulyanchenko, S., Seymour, P.A., Serup, P., Koch, U., Radtke, F., and Blackburn, C.C. (2019) Canonical NOTCH signaling controls the early progenitor state and emergence of the medullary epithelial lineage in fetal thymus development. BIORXIV/2019/600833
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