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

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 and Dominik Filipp ()
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Matouš Vobořil: Institute of Molecular Genetics of the Czech Academy of Sciences
Tomáš Brabec: Institute of Molecular Genetics of the Czech Academy of Sciences
Jan Dobeš: Institute of Molecular Genetics of the Czech Academy of Sciences
Iva Šplíchalová: Institute of Molecular Genetics of the Czech Academy of Sciences
Jiří Březina: Institute of Molecular Genetics of the Czech Academy of Sciences
Adéla Čepková: Institute of Molecular Genetics of the Czech Academy of Sciences
Martina Dobešová: Institute of Molecular Genetics of the Czech Academy of Sciences
Aigerim Aidarova: Institute of Molecular Genetics of the Czech Academy of Sciences
Jan Kubovčiak: Institute of Molecular Genetics of the Czech Academy of Sciences
Oksana Tsyklauri: Institute of Molecular Genetics of the Czech Academy of Sciences
Ondřej Štěpánek: Institute of Molecular Genetics of the Czech Academy of Sciences
Vladimír Beneš: EMBL, Services & Technology Unit
Radislav Sedláček: Institute of Molecular Genetics of the Czech Academy of Sciences
Ludger Klein: Institute for Immunology, Ludwig-Maximilans-Universitat
Michal Kolář: Institute of Molecular Genetics of the Czech Academy of Sciences
Dominik Filipp: Institute of Molecular Genetics of the Czech Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-16081-3

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