Research Aims & Objectives
Thymus development and regeneration
We seek to:
- understand the cellular and molecular pathways underpinning normal thymic stromal development and hence the conditions that enable the regular generation of T cells with a self-tolerant antigen receptor repertoire
- use different gene targeted mouse models that model human thymus stromal pathologies to decipher the importance of distinct embryonic programmes in shaping the complexity of the thymus stromal compartment
- employ genetic pathways identified to be critical during thymus organogenesis to delay the organ’s postnatal senescence and to rejuvenate its capacity for normal thymopoiesis following chemo-radiotherapeutic injury.
- target thymic epithelial cells by different means, including in vivo methods, to change their genetic programmes
Details of research interests
We study the development and function of the thymus and focus on the role of the thymic stromal compartment to develop and select an operative repertoire of T cells. We will use molecular and cellular studies in mice to understand the individual developmental programmes that define cell lineage commitment, differentiation, maintenance and senescence of the different thymic stromal cells. A detailed understanding of the normal developmental program is expected to identify therapeutic targets that enhance thymic regeneration after injury and the ex vivo manufacturing of bespoke microenvironments that allow the differentiation and selection of therapeutic T cells.
We endeavour to gain a detailed understanding of the precursor::progeny relationships and the molecular pathways that enable thymus organogenesis and determine the organ’s function. This information will be used to identify evolutionarily conserved programmes that secure the normal formation and function of the thymus. In parallel, insight from these studies will be used to identify the molecular cause of human pathologies that affect the thymus stromal compartment and form the basis for efforts directed at their correction.
The thymic stroma is composed of different cell types derived from all three germ layers including endodermal epithelia, mesodermal mesenchyme and ectoderm-derived neural-crest cells. The transcription factor FOXN1 acts in a gene-dosage sensitive way as a master regulator of thymic epithelial cell development and maintenance. Thymic epithelia are a major stromal component and essential for the attraction, differentiation, selection and final maturation of blood-borne precursors to functionally competent T cells. The functional absence of FOXN1 causes the “nude” phenotype, a severe combined immunodeficiency marked by athymia. Given its central importance, we investigate the molecular mechanism and dynamics of FOXN1 throughout development and investigate “drug-able” pathways that modulate its expression and function.
Our studies of early thymus development and strategies to regenerate the thymic epithelial compartment are part of a Wellcome Trust funded consortium dedicated to create a fully functional synthetic thymus, built upon in vitro generated thymic epithelial cells. Our contributions are to establish a refined roadmap of the genetic and epigenetic details of thymic epithelial cell development that serves as a blueprint for the generation of an artificial thymus. The availability of such platform will enable the generation of T cell subsets with bespoke functions that can be employed specifically to direct beneficial and modulate adverse immune responses as a new class of therapeutic agents.
Georg A. Holländer
- Fatima Dhalla
- Stefano Maio
- Stanley Cheuk
- Adam Handel
- Fabian Klein
- Jeanette Baran-Gale
- Kirolous Hannah
- Lindsey Rosen
- Mary Deadman - Lab Manager
- Sabrina Harris - Personal Assistant
Collaborators - Oxford:
- Jon Chapman, University of Oxford “Mathematical Modelling”
- Opher Gileadi, Target Discovery Institute – University of Oxford “Crytallography and Proteomics”
Collaborators - External:
- Kenneth Weinberg, Stanford University “11q11 Deletion Syndrome”
- Graham Anderson, University of Birmingham UK “Thymus Biology”
- Chris Ponting, MRC Human Genetics Unit – University of Edinburgh “Bioinformatics”
- Thierry Voet, Department of Human Genetics – KU Leuven “High Through-Put Single T Cell and TCR Analysis”
- Avinash Bhandoola, Laboratory of Genome Integrity – NIH Bethesda USA “Genetics of Thymus Development and Function”
- Wellcome Trust
- Swiss National Science Foundation
- The MRC
- Stanford University 22q11 consortium
We engage with the public via media articles, interviews, and public lectures to disseminate our findings to interested, non-expert audiences. We welcome sixth-form students to gain experience in a research lab and provide students from other Universities opportunities to work on projects as part of internships.