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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Immunological Tolerance and Regulation
Volume 14 - 2023 | doi: 10.3389/fimmu.2023.1277365

Ehf and Fezf2 regulate late medullary thymic epithelial cell and thymic tuft cell development

Sören Lammers1 Victor Barrera2 Philip Brennecke3 Corey Miller4 Joon J. Yoon2 Jared Balolong4 Mark S. Anderson4 Shannan J. Ho Sui2 Lars M. Steinmetz3 Ulrich H. von Andrian5 Kristin Rattay6*
  • 1Institute for Theoretical Physics, Heidelberg University, Germany
  • 2School of Public Health, Harvard University, United States
  • 3Departments of Genetics, School of Medicine, Stanford University, United States
  • 4Diabetes Center, Medical Center, University of California, San Francisco, United States
  • 5Harvard Medical School, United States
  • 6University of Marburg, Germany

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Thymic epithelial cells are indispensable for T cell maturation, selection and the induction of central immune tolerance. The self-peptide repertoire expressed by medullary thymic epithelial cells is in part regulated by the transcriptional regulator Aire (Autoimmune regulator) and the transcription factor Fezf2. Due to the high complexity of mTEC maturation stages (i.e. post-Aire, Krt10+ mTECs and Dclk1+ Tuft mTECs) and the heterogeneity in their gene expression profiles (i.e. mosaic expression patterns) it has been challenging to identify the additional factors complementing the transcriptional regulation. We aimed at identifying the transcriptional regulators involved in the regulation of mTEC development and self-peptide expression in an unbiased and genome wide manner. We used ATAC footprinting analysis as an indirect approach to identify transcription factors involved in the gene expression regulation in mTECs which we validated by ChIP sequencing. This study identifies Fezf2 as regulator of the recently described thymic Tuft cells (i.e., Tuft mTECs). Further, we identify transcriptional regulators of the ELF, ESE, ERF and PEA3 subfamily of the ETS transcription factor family, and members of the Krüppel-like family of transcription factors to play a role in the transcriptional regulation of genes involved in late mTEC development and promiscuous gene expression.

Keywords: Thymus, Central Tolerance, medullary thymic epithelial cell, Tuft-cells, Fezf2, EHF

Received: 14 Aug 2023; Accepted: 29 Dec 2023.

Copyright: © 2023 Lammers, Barrera, Brennecke, Miller, Yoon, Balolong, Anderson, Ho Sui, Steinmetz, von Andrian and Rattay. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Kristin Rattay, University of Marburg, Marburg, Germany