Medullary thymic epithelial cells (mTECs) regulate immune self-tolerance by producing and presenting self-antigen peptides to developing T cells, ensuring self-reactive T cells are inactivated/deleted to prevent autoimmunity. This is controlled by the transcription factor Aire, which promotes genome-wide expression to produce the self-antigen pool utilized by mTECs. My primary goal is to leverage advancements in single-cell transcriptomic profiling and computational immunology to further investigate the core mechanisms of the immune system responsible for ensuring self-tolerance. With this technique we can better understand the degree to which self-tissue information is represented within individual cells and groups of cells. Additionally, studying the developmental lineage of Aire-expressing cells using transcriptomics will provide insight into the regulatory factors that give rise to Aire-expressing mTECs and the contributions of post-Aire terminally differentiated mTECs to immune tolerance. Finally, recent studies have described populations of extra-thymic Aire expressing cells with high transcriptional similarity to mTECs. Further investigation of these shared transcriptional programs will help elucidate previously unappreciated mechanisms responsible for maintaining immune self-tolerance after mature T cells leave the thymus.