Activation of the non-classical NF-kB pathway in thymic epithelial cells drives mTEC development in the absence of TCR+ thymocytes (64.14)

Abstract

Abstract Activation of the non-classical NF-kB signaling pathway is required for the formation of a normal medullary thymic epithelial cell (mTEC) compartment, critical for tolerizing developing thymocytes. Mice deficient for key signaling molecules in this pathway fail to support normal mTEC expansion and differentiation. Known activators of this signaling pathway include tumor necrosis receptor family members; of these, Rank, CD40 and LTbR are all expressed on mTEC and have been shown to be important at various stages of mTEC organization, expansion and differentiation. The ligands for these receptors: RankL, CD40L and LT are provided by TCR-expressing thymocytes; in the absence of TCR+ thymocytes medullary formation is substantially impaired. To test directly whether activation of the non-classical pathway would be sufficient to support mTEC development independently of receptor signaling we made use of a mouse model in which Traf3, a negative regulator of the non-classical NK-kB pathway, is conditionally deleted only in epithelial cells. In B cells where Traf3 has been deleted, constitutive activation of the non-classical NF-kB pathway has been observed in the absence of receptor signaling.We find that epithelial-cell specific Traf3 null mice develop a robust mTEC compartment even in the absence of TCR+ thymocytes, suggesting that engagement of the non-classical NF-kB pathway in mTEC progenitor cells is the critical signal provided by TCR+ thymocytes to promote mTEC formation.