Integrative analysis of scRNA-seq and scATAC-seq revealed transit-amplifying thymic epithelial cells expressing autoimmune regulator

Author:

Miyao Takahisa12,Miyauchi Maki12,Kelly S Thomas3ORCID,Terooatea Tommy W3,Ishikawa Tatsuya12,Oh Eugene1ORCID,Hirai Sotaro1,Horie Kenta1,Takakura Yuki1,Ohki Houko12,Hayama Mio12,Maruyama Yuya12,Seki Takao1,Ishii Hiroto12,Yabukami Haruka3,Yoshida Masaki4,Inoue Azusa5,Sakaue-Sawano Asako6,Miyawaki Atsushi6,Muratani Masafumi7ORCID,Minoda Aki3,Akiyama Nobuko1ORCID,Akiyama Taishin12ORCID

Affiliation:

1. Laboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences

2. Immunobiology, Graduate School of Medical Life Science, Yokohama City University

3. Laboratory for Cellular Epigenomics, RIKEN Center for Integrative Medical Sciences

4. YCI Laboratory for Immunological Transcriptomics, RIKEN Center for Integrative Medical Sciences

5. YCI Laboratory for Metabolic Epigenetics, RIKEN Center for Integrative Medical Sciences

6. Laboratory for Cell Function Dynamics, RIKEN Center for Brain Science

7. Transborder Medical Research Center, and Department of Genome Biology, Faculty of Medicine, University of Tsukuba

Abstract

Medullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by the transcriptional regulator, AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase-accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules, CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected using Fucci technology express a minimal number of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit-amplifying Aire+mTEC precursors during the Aire+mTEC differentiation process of the postnatal thymus.

Funder

Japan Society for the Promotion of Science

Princess Takamatsu Cancer Research Fund

Uehara Memorial Foundation

NOVARTIS Foundation

Ministry of Education, Culture, Sports, Science and Technology

Japan Science and Technology Agency

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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