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Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Olov Ekwall, University of Gothenburg, Sweden
- Second opponent: Professor Simona Chera, University of Bergen
- Third member and chair of the evaluation committee: Associate Professor Asbjørn Otto Christophersen, University of Oslo
Chair of the Defence
Professor Shuo-Wang Qiao, University of Oslo
Principal Supervisor
Professor Benedicte Alexandra Lie, University of Oslo
Summary
During development in the thymus, immature T cells, or thymocytes, undergo selection to ensure that only those without self-reactive potential complete maturation. Self-reactive thymocytes may alternatively diverge into unconventional, agonist selected T cell lineages. Unconventional T cells have immune-modulating functions, and hold potential for cell-based therapies for patients with autoimmune disease. However, their development, regulation, and cellular heterogeneity must be understood for safe and effective implementation.
The aim of this thesis was to enhance current understanding of thymocyte development and selection, emphasising cells undergoing agonist selection and the implicated antigen-presenting and stromal cell populations. Single-cell and spatially resolved technologies were used to characterise cells from young paediatric thymi, permitting elucidation of gene expression profiles, immune receptor repertoires, chromatin landscapes, and spatial organisation.
The findings indicate that divergence into two unconventional T cell lineages, regulatory T cells (Tregs) and CD8αα T cells, occur prior to differentiation of mature, conventional T cells. For Tregs, a second developmental pathway at a later developmental time point was also suggested. Divergence at distinct time points was proposed to be influenced by signalling from distinct populations of antigen-presenting and stromal cells. These populations, in particular thymic epithelial cells, were assessed in detail, revealing previously unrecognised heterogeneity. Further, T cell receptors (TCRs) on the suggested CD8αα precursors exhibited features previously described for TCRs on mature CD8αα T cells, implying that the TCR may also influence developmental decisions.
Overall, the studies increased understanding of factors implicated in development of unconventional T cell populations, which may facilitate future effort towards therapeutic implementations.
Additional information
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