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

• DOI: 10.1038/s41467-020-16081-3
• Publication Date: 2020-05-12T10:08:48Z
• Authors: Matouš Vobořil; Tomáš Brabec; Jan Dobeš; Iva Šplíchalová; Jiří Březina; Adéla Čepková; Martina Dobešová; Aigerim Aidarova; Jan Kubovčiak; Oksana Tsyklauri; Ondřej Štěpánek; Vladimír Beneš; Radislav Sedláček; Ludger Klein; Michal Kolář; Dominik Filipp
• Keywords: 0301 basic medicine; Science; Lipopolysaccharide Receptors; Cell Separation; Thymus Gland; Autoantigens; T-Lymphocytes, Regulatory; Article; Mice; 03 medical and health sciences; Animals; Receptors, Immunologic; Antigen Presentation; Sequence Analysis, RNA; Q; Epithelial Cells; Dendritic Cells; Colitis; Flow Cytometry; Adoptive Transfer; Disease Models, Animal; Self Tolerance; Chemokines; Single-Cell Analysis; Signal Transduction

AbstractThe 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.