Projects per year
Abstract
Thymus medulla epithelium establishes immune self-tolerance and comprises diverse cellular subsets. Functionally relevant medullary thymic epithelial cells (mTECs) include a self-antigen-displaying subset that exhibits genome-wide promiscuous gene expression promoted by the nuclear protein Aire and that resembles a mosaic of extrathymic cells including mucosal tuft cells. An additional mTEC subset produces the chemokine CCL21, thereby attracting positively selected thymocytes from the cortex to the medulla. Both self-antigen-displaying and thymocyte-attracting mTEC subsets are essential for self-tolerance. Here we identify a developmental pathway by which mTECs gain their diversity in functionally distinct subsets. We show that CCL21-expressing mTECs arise early during thymus ontogeny. Fate-mapping analysis reveals that self-antigen-displaying mTECs, including Aire-expressing mTECs and thymic tuft cells, are derived from CCL21-expressing cells. The differentiation capability of CCL21-expressing embryonic mTECs is verified in reaggregate thymus experiments. These results indicate that CCL21-expressing embryonic mTECs carry a developmental potential to give rise to self-antigen-displaying mTECs, revealing that the sequential conversion of thymocyte-attracting subset into self-antigen-displaying subset serves to assemble functional diversity in the thymus medulla epithelium.
Original language | English |
---|---|
Publisher | bioRxiv |
DOIs | |
Publication status | Published - 4 Oct 2023 |
Bibliographical note
Acknowledgments:We thank Drs. Takashi Amagai and Manami Itoi for providing anti-Foxn1 antibody, Dr. Thomas Boehm for providing Foxn1-GFP transgenic mice, Drs. Toyomasa Katagiri, Hitomi Kyuma, Eri Ootsu, Bao Tran, and Assiatu Crossman for technical assistance, and Drs. Alfred Singer, Richard Hodes, Mami Matsuda-Lennikov and Jie Li for reading the manuscript. This work was supported by the Intramural Research Program ZIA BC 011806 of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research (Y.T.); by the JSPS KAKENHI 22K06900, the JSPS Bilateral Program 120219928, and the JST PRESTO Grant 22712940 (I.O.); and by the MRC Programme Grant MR/T029765/1 and the Wellcome Trust Collaborative Award SynThy 211944/Z/18/Z (G.A.).
Fingerprint
Dive into the research topics of 'Developmental conversion of thymocyte-attracting cells into self-antigen-displaying cells in embryonic thymus medulla epithelium'. Together they form a unique fingerprint.Projects
- 1 Active
-
Targeting New Mechanisms In The Control Of Thymus Function To Restore Balanced T-cell Production
1/01/21 → 31/12/25
Project: Research Councils