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

2016 ◽  
Vol 213 (8) ◽  
pp. 1441-1458 ◽  
Author(s):  
Nobuko Akiyama ◽  
Nobukazu Takizawa ◽  
Maki Miyauchi ◽  
Hiromi Yanai ◽  
Ryosuke Tateishi ◽  
...  

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.

2013 ◽  
Vol 190 (10) ◽  
pp. 5110-5117 ◽  
Author(s):  
Enkhsaikhan Lkhagvasuren ◽  
Mie Sakata ◽  
Izumi Ohigashi ◽  
Yousuke Takahama

2009 ◽  
Vol 88 (1) ◽  
pp. 50-56 ◽  
Author(s):  
Živana Milićević ◽  
Novica M Milićević ◽  
Martti Laan ◽  
Pärt Peterson ◽  
Kai Kisand ◽  
...  

Immunobiology ◽  
2013 ◽  
Vol 218 (4) ◽  
pp. 554-560 ◽  
Author(s):  
Claudia Macedo ◽  
Adriane F. Evangelista ◽  
Márcia M. Marques ◽  
Shirlei Octacílio-Silva ◽  
Eduardo A. Donadi ◽  
...  

2021 ◽  
Author(s):  
Max J Duarte ◽  
Romario S Mascarenhas ◽  
Amanda F Assis ◽  
Pedro P Tanaka ◽  
Cesar A Speck-Hernandez ◽  
...  

The autoimmune regulator (Aire) gene in medullary thymic epithelial cells (mTECs) encodes the AIRE protein, which interacts with its partners within the nucleus. This Aire complex induces stalled RNA Pol II on chromatin to proceed with transcription elongation of a large set of messenger RNAs and microRNAs. Considering that RNA Pol II also transcribes long noncoding RNAs (lncRNAs), we hypothesized that Aire might be implicated in the upstream control of this RNA species. To test this, we employed a loss-of-function approach in which Aire knockout mTECs were compared to Aire wild-type mTECs for lncRNA transcriptional profiling both in vitro and in vivo model systems. RNA sequencing enables the differential expression profiling of lncRNAs when these cells adhere in vitro to thymocytes or do not adhere to them as a way to test the effect of cell adhesion. Sets of lncRNAs that are unique and that are shared in vitro and in vivo were identified. Among these, we found the Aire-dependent lncRNAs as for example, Platr28, Ifi30, Morrbid, Malat1, and Xist. This finding represents the first evidence that Aire mediates the transcription of lncRNAs in mTECs. Microarray hybridizations enabled us to observe that temporal thymocyte adhesion modulates the expression levels of such lncRNAs as Morrbid, Xist, and Fbxl12o after 36h of adhesion. This finding shows the existence of a synergistic mechanism involving a link between thymocyte adhesion, Aire, and lncRNAs in mTECs that might be important for immune self-representation.


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