Thymic epithelial β‐catenin is required for adult thymic homeostasis and function

• Published in: Immunology and cell biology Vol. 91; no. 8; pp. 511 - 523
• Main Authors: Liang, Chih‐Chia, You, Li‐Ru, Yen, Jeffrey JY, Liao, Nan‐Shih, Yang‐Yen, Hsin‐Fang, Chen, Chun‐Ming
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.09.2013
• Subjects: Animals; Atrophy - genetics; Bcl2; beta Catenin - genetics; beta Catenin - metabolism; Cells, Cultured; Cytokines - metabolism; Epithelium - immunology; Epithelium - metabolism; Genes, bcl-2 - genetics; IL‐7; keratin 5; keratin 8; Keratin-5 - genetics; Keratin-5 - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Precursor Cells, T-Lymphoid - immunology; T-Lymphocytes - immunology; thymic epithelial cells; thymocytes; Thymocytes - immunology; Thymus Gland - growth & development; Thymus Gland - pathology; Transcription, Genetic - genetics
• ISSN: 0818-9641; 1440-1711
• DOI: 10.1038/icb.2013.34

The role of β‐catenin in thymocyte development has been extensively studied, however, the function of β‐catenin in thymic epithelial cells (TECs) remains largely unclear. Here, we demonstrate a requirement for β‐catenin in keratin 5 (K5)‐expressing TECs, which comprise the majority of medullary TECs (mTECs) and a progenitor subset for cortical TECs (cTECs) in the young adult thymus. We found that conditionally ablated β‐catenin in K5+‐TECs and their progeny cells resulted in thymic atrophy. The composition of TECs was also aberrantly affected. Percentages of K5hiK8+‐TECs, K5+K8–‐TECs and UEA1+‐mTECs were significantly decreased and the percentage of K5loK8+‐TECs and Ly51+‐cTECs were increased in β‐catenin‐deficient thymi compared with that in the control thymi. We also observed that β‐catenin‐deficient TEC lineage could give rise to K8+‐cTECs more efficiently than wild‐type TECs using lineage‐tracing approach. Importantly, the expression levels of several transcription factors (p63, FoxN1 and Aire), which are essential for TEC differentiation, were altered in β‐catenin‐deficient thymi. Under the aberrant differentiation of TECs, development of all thymocytes in β‐catenin‐deficient thymi was impaired. Interleukin‐7 (IL‐7) and chemokines (Ccl19, Ccl25 and Cxcl12) levels were also downregulated in the thymic stromal cells in the mutants. Finally, introducing a BCL2 transgene in lymphoid lineages, which has been shown to rescue IL‐7‐deficient thymopoiesis, partially rescued the thymic atrophy and thymocyte development defects caused by induced ablation of β‐catenin in K5+‐TECs. Collectively, these findings suggest that β‐catenin is required for the differentiation of TECs, thereby contributing to thymocyte development in the postnatal thymus.