Medullary thymic epithelial cells and CD8α dendritic cells coordinately regulate central tolerance but CD8α cells are dispensable for thymic regulatory T cell production.

In the thymus, antigen presenting cells (APCs) namely, medullary thymic epithelial cells (mTECs) and thymic dendritic cells (tDCs) regulate T cell tolerance through elimination of autoreactive T cells and production of thymic T regulatory (tTreg) cells. How the different APCs in the thymus share the burden of tolerazing the emerging T cell repertoire remains unclear. For example, while mutations that inhibit mTEC development or function associate with peripheral autoimmunity, the role of tDCs in organ-specific autoimmunity and tTreg cell production remains controversial. In this report we used mice depleted of mTECs and/or CD8α DCs, to examine the contributions of these cell populations in thymic tolerance. We found that while mice depleted of CD8α DCs or mTECs were normal or developed liver inflammation respectively, combined depletion of mTECs and CD8α DCs resulted in overt peripheral autoimmunity. The autoimmune manifestations in mice depleted of both mTECs and CD8α cDCs associated with increased percentages of CD4 and CD8 T cells in the thymus. In contrast, while mTEC depletion resulted in reduced percentages of tTreg cells, no additional effect was observed when CD8α DCs were also depleted. These results reveal that: 1) mTECs and CD8α DCs cooperatively safeguard against peripheral autoimmunity through thymic T cell deletion; 2) CD8α DCs are dispensable for tTreg cell production, whereas mTECs play a non-redundant role in this process; 3) mTECs and CD8α DCs make unique contributions to tolerance induction that cannot be compensated for by other thymic APCs such as migratory SIRPα or plasmacytoid DCs.