The thymus is the primary lymphoid organ for the generation of naïve T cells. The laboratory’s scientific focus is to define the genetic control of thymus development and function in health and disease. Using molecular, cellular, imaging and computational approaches, our work focuses on identifying the genetic control of normal thymus development and function and to study naturally occurring and targeted mutations causative to compromise the adaptive immune system leading to either severe immunodeficiency or autoimmunity.
The thymic microenvironment is unique in its ability to promote the development of naïve T cells with a repertoire purged of vital “Self” specificities and poised to react to injurious “Non-Self”. Thymic epithelial cells (TECs) constitute the major component of the thymic stroma and can be categorized into separate cortical (c) and medullary (m) lineages based on their specific molecular, structural and functional characteristics. cTEC induce the commitment of blood-borne precursor cells to a T cell fate, foster the subsequent maturation and control the positive selection of antigen receptor bearing thymocytes. In contrast, mTEC promote the terminal differentiation of thymocytes which includes the establishment of immunological tolerance to self-antigens via a deletional mechanism and the generation of natural regulatory T cells.
TEC derive from the endodermal lining of the 3rd pharyngeal pouch and are critically dependent on the transcription factor FOXN1. FOXN1 is a member of the forkhead box (FOX) family of transcription factors, and plays an important role in thymic epithelial cell differentiation and function. FOXN1 mutations in humans and mice give rise to the "nude" phenotype which is characterized by athymia.
Our scientific work focuses on the identification of the genetic circuits that control during development and maintenance the formation of a regular TEC scaffold. For this purpose we have generated several unique gene targeted gain- and loss-of-gene-function models in the mouse. The laboratory’s DPhil projects will take advantage of these distinctive resources and investigate thymus development in these models employing novel analytical methods such as high-parameter single cell spatial imaging and single cell transcriptomics combined with advanced flow cytometry and functional analyses.
The student will learn to design and execute experiments that involve state-of-the art molecular, cellular and imaging methods. In addition, the student will be able to familiarize herself/himself with aspects of computational biology and structural biology.
As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.
All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework.
Funding for this project is available through the WIMM Prize Studentship, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
Applications must be received, including all relevant supporting materials, by Friday 11th January 2019 at 12 noon (midday).
Please visit our website for more information on how to apply.
Žuklys S#1, Handel A#2, Zhanybekova S#1, Govani F3, Keller M1, Maio S3, Mayer CE1, Teh HY1, Hafen K1, Gallone G2, Barthlott T1, Ponting CP2, Holländer GA1,3. Foxn1 regulates key target genes essential for T cell development in postnatal thymic epithelial cells. Nat Immunol. 2016 Oct;17(10):1206-1215. doi: 10.1038/ni.3537. Epub 2016 Aug 22.
Handel AE, Shikama-Dorn N, Zhanybekova S, Maio S, Graedel AN, Zuklys S, Ponting CP, Holländer GA. Comprehensively profiling 1 the chromatin architecture of tissue restricted antigen expression in thymic epithelial cells over development. Front. Immunol., 2018 Sept; 9:2120.doi.org/10.3389/fimmu.2018.02120
Joseph A Newman, Hazel Aitkenhead, Angeline Gavard, Ioanna A Rota, Adam E Handel, Georg A Hollander, Opher Gileadi. The structural basis for forkhead box family specificity revealed by the crystal structure of human FOXN1 in complex with DNA. (submitted)
Sansom SN, Shikama N, Zhanybekova S, Nusspaumer G, Macaulay IC, Deadman ME, Heger A, Ponting CP, Holländer GA. Population and single cell genomics reveal the Aire-dependency, relief from Polycomb silencing and distribution of self-antigen expression in thymic epithelia. Genome Res. 2014, 24:1918-31
Mayer CE, Žuklys S, Zhanybekova S, Ohigashi I, Teh HY, Sansom SN, Shikama-Dorn N, Hafen K, Macaulay IC, Deadman ME, Ponting CP, Takahama Y, Holländer GA. Dynamic spatio-temporal contribution of single β5t+ cortical epithelial precursors to the thymus medulla. Eur J Immunol. 2016, 46:846-56