Autoimmune Regulator (Aire) was originally characterized as a transcriptional regulator expressed in medullary thymic epithelial cells (mTECs). Aire induces expression of tissue specific antigens in mTECs, which is essential for deleting auto-reactive T cells to prevent autoimmune diseases. Interestingly, we have also found Aire-expressing cells outside of thymus in secondary lymphoid organs. These extrathymic Aire-expressing cells (eTACs) have transcriptional similarity to mTECs and migratory dendritic cells and have a tolerogenic signature. Self-antigen expression in eTACs is sufficient to prevent autoimmunity by inducing T cell tolerance. However, function of Aire in these populations is still largely unknown, mostly due to the lack of tools for studying these cells specifically outside of the thymus. By generating various conditional knockout mice where they only lack Aire in the periphery, we will precisely study the function of Aire in eTACs and investigate the role of extrathymic Aire in maintaining peripheral immune homeostasis. Overall, this research is not only important for understanding the biology of this complex transcriptional regulator but could be clinically significant for many implications such as autoimmunity, cancer, and maternal-fetal tolerance.