Identification of mTEC precursor cells
Akiyama, Nobuko The University of Tokyo
Takizawa, Nobukazu The University of Tokyo
Miyauchi, Maki The University of Tokyo
Yanai, Hiromi The University of Tokyo
Tateishi, Ryosuke The University of Tokyo
Shinzawa, Miho The University of Tokyo
Yoshinaga, Riko The University of Tokyo
Kurihara, Masaaki National Institute of Health Sciences
Demizu, Yosuke National Institute of Health Sciences
Yasuda, Hisataka Oriental Yeast Co., Ltd.
Yagi, Shintaro The University of Tokyo
Wu, Guoying The University of Tokyo
Sakamoto, Reiko The University of Tokyo
Yoshida, Nobuaki The University of Tokyo
Penninger, Josef M. Institute of Molecular Biotechnology of the Austrian Academy of Sciences
Kobayashi, Yasuhiro Matsumoto Dental University
Inoue, Jun-ichiro The University of Tokyo
Akiyama, Taishin The University of Tokyo
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.
Journal of Experimental Medicine
Rockefeller University Press
© 2016 Akiyama et al.
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