Translational studies of sex differences in human thymic central tolerance induction

Abstract

Sex is a fundamental biological variable influencing human immune function. Females exhibit more robust responses to both self- and non-self-antigens than males which manifest as higher prevalence of autoimmune disease, whereas men mount less effective responses to infection and cancer. Both hormonal and genetic factors have been suggested to contribute, yet the exact mechanisms driving sex differences in immunological phenotypes remain incompletely understood. The establishment of central tolerance occurs in the thymus, the key organ responsible for this process. This thesis aimed to test the hypothesis that sex-based differences in thymic central tolerance induction contribute to the observed female predominance in autoimmune diseases. Additionally, we aimed to characterize key aspects of thymic stromal development and function by examining the thymus in the 22q11.2 deletion syndrome (22q11DS). In Paper I, we used whole exome sequencing, RNA sequencing and epigenetic analyses to examine X-chromosome inactivation in human thymocytes. We found that X-inactivation remains highly stable throughout human T-cell development, challenging the prevailing view that genes escaping X-inactivation is essential during normal T cell development. In Paper II, we integrated spatial transcriptomics and spatial proteomics to characterize sex-specific differences in human thymic architecture and function. In Paper III, we applied the same approach for spatial analyses of thymic tissue from patients with 22q11DS, with findings underscoring the importance of stromal-epithelial crosstalk in maintaining normal human thymic function and nominating stromal remodeling as a potential driver of impaired central tolerance induction in 22q11DS.