Functionally diverse thymic medullary epithelial cells interplay to direct central tolerance

Medullary thymic epithelial cells (mTECs) are essential for the establishment of self-tolerance in T cells. Promiscuous gene expression by a subpopulation of mTECs regulated by the nuclear protein Aire contributes to the display of self-genomic products to newly generated T cells. Recent reports have highlighted additional self-antigen-displaying mTEC subpopulations, namely Fezf2-expressing mTECs and a mosaic of self-mimetic mTECs including thymic tuft cells. In addition, a functionally different subset of mTECs produces chemokine CCL21, which attracts developing thymocytes to the medullary region. Here, we report that CCL21+ mTECs and Aire+ mTECs non-redundantly cooperate to direct self-tolerance to prevent autoimmune pathology by optimizing the deletion of self-reactive T cells and the generation of regulatory T cells. We also detect cooperation for self-tolerance between Aire and Fezf2, the latter of which unexpectedly regulates thymic tuft cells. Our results indicate an indispensable interplay among functionally diverse mTECs for the establishment of central self-tolerance. [Display omitted] •Mice lacking CCL21+ mTECs and Aire+ mTECs exhibit a severe autoimmunity in C57BL/6 background•CCL21+ mTECs and Aire+ mTECs cooperate for autoreactive T cell deletion and Treg cell generation•Fezf2 has a modest but significant role in central tolerance in mice•Fezf2 regulates a fraction of mimetic mTECs including thymic tuft cells Ushio et al. show that functionally diverse medullary thymic epithelial cell (mTEC) subpopulations cooperate to prevent autoimmune pathology. The results demonstrate the interplay between diverse mTEC subpopulations, namely between CCL21+ mTECs and Aire+ mTECs and between Aire+ mTECs and Fezf2+ mTECs, for optimizing central tolerance.