Student Projects in the Laboratory of Development Immunology (Paediatrics)
Supervisor: Prof Georg Hollander
T cell mediated responses play a crucial role in providing protective immunity against microbial pathogens and transformed cells, but when directed against self, are responsible for a broad range of debilitating autoimmune and inflammatory diseases. The thymus serves as the primary lymphoid organ for the physiological development of T cells and hence is critical for the successful establishment and maintenance of the immune system's capacity to distinguish between vital “Self” and injurious “Non-Self”. Its key role is emphasised by the lack of an adaptive immune response in athymic individuals (e.g. congenital Foxn1 deficiency) and in-born as well as acquired deficiencies in Self/Non-Self discrimination that lead to a broad spectrum of autoimmune pathologies.
The stromal compartment of the thymus is predominantly composed of thymic epithelial cells (TEC) that are further distinguished into cortical and medullary TEC subpopulations based on distinct phenotypic and functional features. TEC are derived exclusively from the endodermal lining of the ventral aspects of the third pharyngeal pouch by developmental programmes that are, however, not yet fully characterized. For example, the forkhead transcription factor Foxn1 is the first recognizable marker of a commitment to the TEC fate but its specific role during subsequent stages of TEC differentiation and its function in the maintenance of the epithelial scaffold remain poorly understood. A cell’s individual identity is in addition to the expression of individual transcription factors also controlled by lineage-determining and stage-specific epigenetic mechanisms including post-transcriptional histone modifications, microRNA (miRNA) and long intergenic non-coding RNA (lincRNA). However, very little is known regarding the epigenetics of TEC biology.
In addition to their role during early intra-thymic T cell development, TEC are also essential for the shaping of the repertoire of antigen specificities expressed by mature T cells. Because their initial generation is random, T cell antigen receptors (TCR) need to be selected for their functionality and usefulness for a given individual. That is the repertoire of TCR specificities is specifically selected to be non-responsive to the organism’s own range of antigens (designated Self) whilst simultaneously able to elicit an immune response to Non-Self (i.e. foreign) antigens. This essential selection of the TCR repertoire is effected by both cortical and medullary TEC. However, the mechanisms how TEC control this selection process awaits a detailed description at the molecular level.
A detailed understanding of the molecular and cellular control of TEC lineage commitment, differentiation and function is essential for the assessment of the normal and pathological stages of thymus development and for efforts to regenerate thymus structure and function both in vitro and in vivo.
The research programme of the Developmental Immunology Group at the MRC Weatherall Institute of Molecular Medicine is focused on defining genetic and epigenetic control of thymus organogenesis and function. Specifically, our research is focused on the following areas:
- To understand the central role of the transcription factor Foxn1, its target genes and specific signalling pathways in distinct thymus epithelial cell subpopulations at precise developmental stages.
- To determine the mechanism by which TEC are able to promiscuously express tissue specific antigens for the purpose of TCR repertoire selection
- To identify the molecular mechanisms that enable thymic epithelial cells to effect efficient positive and negative selection of developing thymoctes to achieve a normal antigen receptor repertoire among naïve, mature T cells.
For this purpose, state-of-the-art molecular and cellular tools are applied to informative experi-mental systems and clinical samples.
For further information please contact: Prof Georg Hollander