Toll-like receptor signaling in thymic epithelium controls monocyte-derived dendritic cell recruitment and Treg generation

The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14(+)Sirpα(+) population of monocyte-derived dendritic cells (CD14(+)moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14(+)moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25(+)Foxp3(+) Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14(+)moDC, the generation of Tregs, and thereby the establishment of central tolerance.