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Until now, the mechanism that regulates the survival of TECs is poorly understood. In the current study, we found that Tsc1 controls the homeostasis of medullary TECs (mTECs) by inhibiting lysosomal-mediated apoptosis pathway in mice. TEC-specific deletion of Tsc1 predominately decreased the cell number of mTECs and, to a lesser content, affected the development cortical TECs. The defect of mTECs caused by Tsc1 deficiency in mice impaired thymocyte development and peripheral T cell homeostasis. Mechanistically, Tsc1 deficiency did not affect the cell proliferation of mTECs but increased the apoptosis of mTECs significantly. RNA-sequencing analysis showed that pathways involved in lysosomal biogenesis, cell metabolism, and apoptosis were remarkably elevated in Tsc1-deficient mTECs compared with their wild-type counterparts. Tsc1-deficient mTECs exhibited overproduction of reactive oxygen species and malfunction of lysosome, with lysosome membrane permeabilization and the release of cathepsin B and cathepsin L to the cytosol, which then lead to Bid cleaved into active truncated Bid and subsequently intrinsic apoptosis. Finally, we showed that the impaired development of mTECs could be partially reversed by decreasing mTORC1 activity via haploinsufficiency of Raptor. Thus, Tsc1 is essential for the homeostasis of mTECs by inhibiting lysosomal-mediated apoptosis through mTORC1-dependent pathways.<\/jats:p>","DOI":"10.4049\/jimmunol.2100463","type":"journal-article","created":{"date-parts":[[2021,9,17]],"date-time":"2021-09-17T17:10:29Z","timestamp":1631898629000},"page":"2039-2050","source":"Crossref","is-referenced-by-count":15,"title":["The Development and Survival of Thymic Epithelial Cells Require TSC1-Dependent Negative Regulation of mTORC1 Activity"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0410-2501","authenticated-orcid":false,"given":"Zhanfeng","family":"Liang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5469-4878","authenticated-orcid":false,"given":"Qian","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1568-0857","authenticated-orcid":false,"given":"Zhaoqi","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Dong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianxiu","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Urological Organ Transplantation, The Second Xiangya Hospital, Central South University , Changsha ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xubiao","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Urological Organ Transplantation, The Second Xiangya Hospital, Central South University , Changsha ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liguang","family":"Sun","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, The First Hospital, Jilin University , Changchun ,","place":["China"]},{"name":"National-Local Joint Engineering Laboratory of Animal Models for Human Diseases , Changchun ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2850-3008","authenticated-orcid":false,"given":"Yong","family":"Zhao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"University of Chinese Academy of Sciences , Beijing ,","place":["China"]},{"name":"Institute for Stem Cell and Regeneration, Chinese Academy of Sciences , Beijing ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,15]]},"reference":[{"key":"2025022610321802600_r1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1146\/annurev-immunol-051116-052320","article-title":"Thymic epithelial cells","volume":"35","author":"Abramson","year":"2017","journal-title":"Annu. 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