Psmb11-KO Mouse

Psmb11 encodes the β5t subunit of the thymoproteasome, specifically expressed in cortical thymic epithelial cells (cTECs) [1,2,4,5,6,7]. It is essential for the optimal positive selection of functionally competent CD8+ T cells, and also impacts gene expression in cTECs, mainly via differential proteolysis of transcription factors [1,2]. The genes it regulates in cTECs modulate lymphostromal interactions, primarily through the WNT signaling pathway [2]. Genetic models, such as mouse models, have been crucial in studying its function.

In Psmb11 -/- mice, cTECs acquire features of medullary thymic epithelial cells, retain CD8 thymocytes in the thymic cortex, impair phase 2 of positive selection, perturb CD8 T cell development, and cause oxidative stress leading to apoptosis of CD8 thymocytes [2]. Deletion of Psmb11 also causes oxidative stress in CD4 thymocytes, though they do not undergo apoptosis as they upregulate chaperones and apoptosis inhibitors [2]. Introduction of a human genomic PSMB11 variation into the mouse genome showed that heterozygotes had reduced β5t expression in cTECs and homozygotes had a reduction in CD8+ T cell cellularity [4].

In conclusion, Psmb11 is vital for T cell development, especially for the positive selection of CD8+ T cells. Mouse knockout models have been instrumental in revealing its role in maintaining cTEC distinctness, promoting thymocyte migration, and its impact on CD4 and CD8 thymocyte development. Understanding Psmb11 function may provide insights into autoimmune diseases and T cell-related disorders, as polymorphisms in this gene can potentially affect T cell repertoire selection and individual susceptibility to autoimmunity [3,5].

References:

1. Apavaloaei, Anca, Laverdure, Jean-Philippe, Perreault, Claude. . PSMB11 regulates gene expression in cortical thymic epithelial cells. In Cell reports, 36, 109546. doi:10.1016/j.celrep.2021.109546. https://pubmed.ncbi.nlm.nih.gov/34496243/

2. Apavaloaei, Anca, Brochu, Sylvie, Dong, Mengqi, Melichar, Heather J, Perreault, Claude. 2018. PSMB11 Orchestrates the Development of CD4 and CD8 Thymocytes via Regulation of Gene Expression in Cortical Thymic Epithelial Cells. In Journal of immunology (Baltimore, Md. : 1950), 202, 966-978. doi:10.4049/jimmunol.1801288. https://pubmed.ncbi.nlm.nih.gov/30567730/

3. Marx, Alexander, Yamada, Yosuke, Simon-Keller, Katja, Ströbel, Philipp, Weis, Cleo-Aron. 2021. Thymus and autoimmunity. In Seminars in immunopathology, 43, 45-64. doi:10.1007/s00281-021-00842-3. https://pubmed.ncbi.nlm.nih.gov/33537838/

4. Ohigashi, Izumi, Ohte, Yuki, Setoh, Kazuya, Murata, Shigeo, Takahama, Yousuke. 2017. A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production. In JCI insight, 2, . doi:10.1172/jci.insight.93664. https://pubmed.ncbi.nlm.nih.gov/28515360/

5. Nitta, Takeshi, Kochi, Yuta, Muro, Ryunosuke, Yamamoto, Kazuhiko, Takayanagi, Hiroshi. 2017. Human thymoproteasome variations influence CD8 T cell selection. In Science immunology, 2, . doi:10.1126/sciimmunol.aan5165. https://pubmed.ncbi.nlm.nih.gov/28783658/

6. Sutoh, Yoichi, Kondo, Mizuho, Ohta, Yuko, Flajnik, Martin F, Kasahara, Masanori. 2011. Comparative genomic analysis of the proteasome β5t subunit gene: implications for the origin and evolution of thymoproteasomes. In Immunogenetics, 64, 49-58. doi:10.1007/s00251-011-0558-0. https://pubmed.ncbi.nlm.nih.gov/21748441/

7. Takada, Kensuke, Ohigashi, Izumi, Kasai, Michiyuki, Nakase, Hiroshi, Takahama, Yousuke. . Development and function of cortical thymic epithelial cells. In Current topics in microbiology and immunology, 373, 1-17. doi:10.1007/82_2013_322. https://pubmed.ncbi.nlm.nih.gov/23612989/