Thymocyte requirements for normal thymic medullary epithelial cell development (HEM7P.227)

Abstract

Abstract The thymic medullary compartment has a central role in tolerizing developing TCRαβ+ CD4 and CD8 single positive (SP) thymocytes. In turn, SP thymocytes are required for normal maturation of medullary thymic epithelial cells (mTEC). In the absence of TCRαβ+ SP thymocytes, the thymic medullary compartment is much smaller and numbers of mTEC are dramatically reduced. We recently demonstrated that the requirement for TCRαβ+ SP thymocytes in mTEC development can be overcome when Traf3, an inhibitor of NIK-dependent NF-κB signaling, is absent in TEC. In contrast to TCRα KO mice, TCRα KO/TEC-specific Traf3 KO mice have mTEC numbers comparable to that of wildtype mice. Traf3 inactivation also overcomes the requirements for LTβR and CD40 in mTEC development. Interestingly, however, we find that mTEC cell numbers are not rescued in TCRβ KO/TEC-specific Traf3 KO mice. TCRβ KO mice, like TCRα KO mice, lack SP thymocytes but also lack post-β-checkpoint TCRβ+ DN and DP thymocytes. This result suggests that a cell type(s) other than a TCRαβ+ SP thymocyte is required for normal mTEC development even in the absence of Traf3 and that this requirement is mediated by molecular interactions other than those involving LTβR and CD40. Studies to determine the identity of this thymic cell population and the corresponding molecular pathways involved in mTEC development are underway.