Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator

• Published in: The Journal of experimental medicine Vol. 213; no. 8; pp. 1441 - 1458
• Main Authors: Akiyama, Nobuko, Takizawa, Nobukazu, Miyauchi, Maki, Yanai, Hiromi, Tateishi, Ryosuke, Shinzawa, Miho, Yoshinaga, Riko, Kurihara, Masaaki, Demizu, Yosuke, Yasuda, Hisataka, Yagi, Shintaro, Wu, Guoying, Matsumoto, Mitsuru, Sakamoto, Reiko, Yoshida, Nobuaki, Penninger, Josef M, Kobayashi, Yasuhiro, Inoue, Jun-Ichiro, Akiyama, Taishin
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 25.07.2016
• Subjects: AIRE Protein; Animals; Cell Differentiation - genetics; Cell Differentiation - immunology; Epithelial Cells - cytology; Epithelial Cells - immunology; Gene Expression Regulation - genetics; Gene Expression Regulation - immunology; Mice; Mice, Inbred BALB C; Mice, Knockout; Mouse Embryonic Stem Cells - cytology; Mouse Embryonic Stem Cells - immunology; Plant Lectins - genetics; Plant Lectins - immunology; Thymus Gland - cytology; Thymus Gland - immunology; Transcription Factors - genetics; Transcription Factors - immunology
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20151780

Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire(+) mTECs) is unclear. Here, we describe novel embryonic precursors of Aire(+) mTECs. We found the candidate precursors of Aire(+) mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire(+) mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire(+) mTECs and efficiently suppressed the onset of autoimmunity induced by Aire(+) mTEC deficiency. Mechanistically, pMECs differentiated into Aire(+) mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire(+) mTECs.