AIRE Deficiency Impairs Thymic Epithelial Progenitor Differentiation from Mouse Embryonic Stem Cells and Accelerates Type 1 Diabetes in NOD/Ltj Mice
6 affiliations
- 1Center for Tissue Engineering and Stem Cell Research, Translation Medicine Research Center, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guiyang 561113, China
- 2Department of Human Histology, Embryology and Regenerative Medicine, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guiyang 561113, China
- 3Guizhou Biomanufacturing Laboratory, Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guiyang 561113, China
- 4National Joint Local Engineering Laboratory for Cell Engineering and Biomedicine Technique, 6 Ankang Avenue, Guian New District, Guiyang 561113, China
- 5Key Laboratory of Adult Stem Cell Translational Research (Chinese Academy of Medical Sciences), Guizhou Medical University, 6 Ankang Avenue, Guian New District, Guiyang 561113, China
- 6Key Laboratory for Research on Autoimmune Diseases of Higher Education Schools in Guizhou Province, 6 Ankang Avenue, Guian New District, Guiyang 561113, China
Abstract
The autoimmune regulator (AIRE) is essential for central immune tolerance, but its role in thymic epithelial cell (TEC) differentiation and development remains incompletely understood. To address this, we knocked down AIRE in mouse embryonic stem cells (mESCs) and analyzed thymic epithelial progenitor (TEP) differentiation using RNA-sequencing and also performed thymic AIRE knockdown in NOD/Ltj mice to evaluate type 1 diabetes (T1D) pathogenesis. AIRE knockdown significantly reduced the proportion of K5+/K8+ TEPs among EpCAM1+ cells and altered the ECM–receptor interaction pathway, with downregulation of SPP1 and upregulation of Fn1 and CD44. Importantly, re-expression of AIRE using an shRNA-resistant rescue vector partially reversed these molecular changes and partially restored TEP differentiation. In vivo, thymic AIRE knockdown accelerated blood glucose elevation, aggravated insulitis, and reduced expression of T1D-associated TSAs (INS2, GAD67) and maturation markers (CD80, MHC-II). Importantly, the changes in SPP1, Fn1, and CD44 were consistent between in vitro and in vivo models. Furthermore, AIRE deficiency increased CD4+ single-positive thymocytes, reduced splenic Treg frequency, and enhanced antigen-specific T cell proliferation and activation. Collectively, these findings demonstrate that AIRE deficiency impairs TEP differentiation and alters the ECM-receptor pathway, while thymic AIRE deficiency compromises immune tolerance and accelerates T1D progression in NOD/Ltj mice.
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BibTeX
@article{li2026aire,
title = {{AIRE Deficiency Impairs Thymic Epithelial Progenitor Differentiation from Mouse Embryonic Stem Cells and Accelerates Type 1 Diabetes in NOD/Ltj Mice}},
author = {Yuandi Li and Keke He and Xunru Qu and Jie Gao and Rong Hu and Min Su},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209182},
url = {https://www.mdpi.com/1422-0067/27/20/9182},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - AIRE Deficiency Impairs Thymic Epithelial Progenitor Differentiation from Mouse Embryonic Stem Cells and Accelerates Type 1 Diabetes in NOD/Ltj Mice
AU - Yuandi Li
AU - Keke He
AU - Xunru Qu
AU - Jie Gao
AU - Rong Hu
AU - Min Su
PY - 2026
DA - 2026/10/01
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209182
UR - https://www.mdpi.com/1422-0067/27/20/9182
AB - The autoimmune regulator (AIRE) is essential for central immune tolerance, but its role in thymic epithelial cell (TEC) differentiation and development remains incompletely understood. To address this, we knocked down AIRE in mouse embryonic stem cells (mESCs) and analyzed thymic epithelial progenitor (TEP) differentiation using RNA-sequencing and also performed thymic AIRE knockdown in NOD/Ltj mice to evaluate type 1 diabetes (T1D) pathogenesis. AIRE knockdown significantly reduced the proportion of K5+/K8+ TEPs among EpCAM1+ cells and altered the ECM–receptor interaction pathway, with downregulation of SPP1 and upregulation of Fn1 and CD44. Importantly, re-expression of AIRE using an shRNA-resistant rescue vector partially reversed these molecular changes and partially restored TEP differentiation. In vivo, thymic AIRE knockdown accelerated blood glucose elevation, aggravated insulitis, and reduced expression of T1D-associated TSAs (INS2, GAD67) and maturation markers (CD80, MHC-II). Importantly, the changes in SPP1, Fn1, and CD44 were consistent between in vitro and in vivo models. Furthermore, AIRE deficiency increased CD4+ single-positive thymocytes, reduced splenic Treg frequency, and enhanced antigen-specific T cell proliferation and activation. Collectively, these findings demonstrate that AIRE deficiency impairs TEP differentiation and alters the ECM-receptor pathway, while thymic AIRE deficiency compromises immune tolerance and accelerates T1D progression in NOD/Ltj mice.
SN - 1422-0067
ER -