Developmental immunology: The molecular and cellular biology of thymus development and function

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.