Topoisomerase 1 is required for the development and function of thymus

Abstract Thymus organogenesis is critical for proper maturation of developing T cells. In this study, we identified Top1 as a novel gene involved in thymus development and function. We created a mouse line with deletion of Top1 in thymic epithelial cells (TECs), and our results demonstrate that biallelic loss of Top1 in TECs causes congenital thymic aplasia, precipitating T cell immunodeficiency. Transcriptomic analysis provides insights into the molecular mechanism of Top1 in thymus development as we identify key genes involved in thymus organogenesis as the transcriptional targets of Top1 in TECs. Analysis of peripheral immunological compartments revealed severe loss of αβ T cells complemented with a disproportionate accumulation of γδ T cells and myeloid cells upon deletion of Top1 in TECs. The residual αβ T cells in Top1 knockout mice were effector and oligoclonal in nature highlighting their self-reactivity. These results reveal a previously unknown role of Top1 in thymus development and T cell homeostasis. We propose Top1 as a genetic target for altered thymic development and T cell lymphopenia.