The bicuspid aortic valve (BAV) is a congenital heart defect which is characterized by the formation of two aortic leaflets instead of the normal three leaflets within the tricuspid aortic valve ... Show moreThe bicuspid aortic valve (BAV) is a congenital heart defect which is characterized by the formation of two aortic leaflets instead of the normal three leaflets within the tricuspid aortic valve (TAV). Whilst all BAV patients have a bicuspid valve, extended patient monitoring has revealed a large variation of disease progression trajectories during a patient’s lifetime. This large variation troubles clinical decision making due to the uncertain proliferation of BAV disease. More knowledge of the biological mechanisms underlying BAV could address that uncertainty and thus help stratify patient risk with more accuracy. Therefore this thesis aims to advance our current understanding regarding the biological impact and developmental mechanisms underlying congenital BAV and BAV related aortopathy. Show less
Resident memory CD8+ T cells (CD8+ TRM) play a central role in tissue immunity. This thesis focusses on the formation, function and behavior of CD8+ TRM in the skin. Firstly, by making use of... Show moreResident memory CD8+ T cells (CD8+ TRM) play a central role in tissue immunity. This thesis focusses on the formation, function and behavior of CD8+ TRM in the skin. Firstly, by making use of lineage tracing technology, we show that the capacity to form TRM is instilled in CD8+ T cells before the cells enter the affected tissue and that this capacity remains fixed after a secondary immune challenge. Second, this works shows that CD8+ skin-TRM act as local sentinels that trigger a rapid and tissue-wide immune response upon foreign antigen recognition. Third, ex vivo imaging of human skin biopsies demonstrates that tissue patrol is a property of CD8+ TRM in human skin. In addition, this work describes the development of two novel technologies (i.e. the ‘Tol’ mouse strain and the ex vivo imaging technique) that can be used as such or adapted by other biomedical researchers in order to investigate key aspects of (T) cell behavior and skin biology. Understanding the signals that drive CD8+ TRM formation, and insights in the function of these cells within both healthy and diseased skin, will be essential to allow the manipulation of these populations for therapeutic benefit. Show less
