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Thymopoiesis: From Evolutionary Origins to Future Therapies

Final Report Summary - EVOTHYME (Thymopoiesis: From Evolutionary Origins to Future Therapies)

In the first part of the project, we have conducted the so far largest forward genetic screen undertaken in a vertebrate to identify mutations affecting T cell development. A genetic network analysis of over 40 affected genes together with pharmacological inhibitor screens suggest novel synthetic lethal strategies to modulate the outcome of acute lymphoblastic leukemia (T-ALL). Additional gene-centered analyses provided information, for instance, on transgenerational inheritance of epimutations, the unexpected tissue-specific functions of general-purpose multi-protein complexes involved in DNA replication, and the lineage tree of innate lymphocyte subsets. We also established a new animal model for stable propagation of xenogeneic haematopoietic stem cells in a mutant zebrafish background.
In the second part of the project, we have examined the evolutionary trajectory of the Foxn1/4 transcription factor family, delineated the functional roles of individual protein domains with respect to lymphopoietic capacity, and defined their level of redundancy. This finding provided a framework to help to understand the phenotype of Foxn1 mutations in human immunodeficiency patients. Additional experiments, including a novel CRISPR/Cas9-mediated bar-coding system allowed us to clarify the developmental trajectory of thymic epithelial cell progenitors before and after birth; likewise, our studies have shown that BMP signalling is required to stabilize the fate of newly born TEC progenitor cells, and that FGF signalling promotes their proliferation. Collectively, these findings provide the basis for the prospective isolation of these precursors as a first step towards their therapeutic use in immunodeficiency/autoimmune syndromes
In the third part of the project, combinatorial transgenesis was used to establish the minimal number of factors that robustly increase thymopoietic capacity; dominant roles for the CIITA transactivator and the IL-7 cytokine were identified. We also attempted to invert the functional activities of the pharyngeal derivatives parathyroid and thymus. Whereas the re-programming of the parathyroid into a thymopoietic tissue is complicated by the fact that the cells are overly susceptible to apoptosis, the re-programming of the thymus into a functional parathyroid was successfully achieved, providing important lessons on the process of trans-differentiation in the intact organism.