Control of central self-tolerance induction by autoreactive CD4+ thymocytes

Medullary thymic epithelial cells (mTECs) are crucial for the selection of a T-cell-receptor (TCR) repertoire purged of self-reactive specificities, because these cells activate a promiscuous gene-expression program that leads to the synthesis of a wide array of peripheral tissue-restricted self-antigens. This review summarizes recent progress in our understanding of the cellular interactions, ligands, receptors and signal-transduction pathways that control mature-mTEC development. The particular focus is on new findings supporting the model that mature-mTEC development in the postnatal thymus depends on nuclear factor-κB (NF-κB) signaling induced by CD40–CD40 ligand, and receptor-activator-of-NF-κB (RANK)–RANK ligand interactions, and that these signals are delivered in the context of antigen-specific interactions between CD4+ thymocytes carrying autoreactive TCRs and mTECs displaying cognate autoantigen–MHC-class-II complexes.