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Ribosomal protein S26 serves as a checkpoint of T-cell survival and homeostasis in a p53-dependent manner

Cellular & Molecular Immunology volume 18, pages 1844–1846 (2021)Cite this article

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Ribosomal proteins (RPs), which play critical roles in ribosome assembly and protein translation, have been proven to be associated with important physiological and pathological processes, including the regulation of T-cell development and immune-related diseases.1,2,3 A recent study reported that ribosomal protein S26 (Rps26), which is a Diamond–Blackfan anemia-associated RP located in the 40S subunit that controls oocyte growth,4,5 may influence multiple different immune phenotypes.6 Moreover, a SNP in the 5′ UTR of the Rps26 gene in CD4+ and CD8+ T cells was implicated in several autoimmune diseases.7 However, the function of Rps26 in T lymphocytes remains unknown. Here, we found that Rps26 was highly expressed in T lymphocytes. We examined a T-cell-specific Rps26 knockout mouse model and reported for the first time that ablation of Rps26 in T cells not only impairs peripheral T-cell homeostasis but also leads to T-cell developmental arrest in the thymus. Mechanistically, Rps26 critically regulates T-cell survival in a p53-dependent manner. These findings reveal the indispensable role of the Rps26-p53 axis in T-cell development and homeostasis.

We then further investigated whether the decrease in peripheral T cells was due to the influences of T-cell development in the thymus. The thymus size of the KO mice was smaller than that of the control mice (Fig. S2A), and both the proportion and number of mature CD4+ or CD8+ single-positive (SP) cells were severely decreased in the KO mice (Figs. 1E and S2B). The survival of thymocytes is crucial to their development and maturation. To assess the survival of thymic SP cells, we cultured thymocytes for the indicated times. Flow cytometric analysis revealed a larger number of apoptotic SP cells in the KO mice after 8 and 24 h of in vitro culture (Figs. 1F and S2C). In contrast, the CD4+CD8+ double-positive (DP) and CD4−CD8− double-negative (DN) cells in the thymus were unaffected in our CD4-Cre mouse model, which might be due to incomplete recombination efficiency. To assess the Cre-mediated recombination efficiency in our mouse model, we crossed CD4-Cre mice with mT/mG (membrane-localized tdTomato/membrane-localized EGFP) transgenic mice (Fig. S3A).8 The flow cytometric results showed that as expected, most DN cells, which do not express CD4, were nonrecombinant cells that only expressed the tdTomato fluorescent protein. Moreover, a large proportion of tdTomato and EGFP DP cells were detected in the DP stage (Fig. S3B), verifying that CD4-Cre can induce loxp-mediated recombination, but the protein deletion was not yet completed in the DP stage, which explained why the number of DP and DN cells was unaffected in the CD4-Cre Rps26fl/fl mice. In addition, we did not detect a difference in proliferation (Fig. S2D). Consistently, Rps26-deficient peripheral T cells were more prone to apoptosis than cells from littermate controls (Figs. 1G and S4A). Collectively, the above data demonstrated that Rps26 regulates T-cell survival and development.

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Acknowledgements

This work was supported by Taishan Scholarship (No. tspd20181201), the Major Basic Research Project of Shandong Natural Science Foundation ZR2020ZD12, the National Natural Science Foundation of China (Key program 81830017 to C.M.; Grant 31600714 to C.L.), the China Postdoctoral Science Foundation (Grants 2016M592193 and 2018M642660 to C.L.), the Young Elite Scientist Sponsorship Program by Cast (Grant YESS20160077 to C.L.), the National Postdoctoral Program for Innovative Talents (Grant BX201700147 to C.L.), and the Young Scholars Program of Shandong University (to C.L.). We thank the Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.

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  1. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Immunology, School of Basic Medical Science, Shandong University, Jinan, Shandong, PR China

    Chaojia Chen, Jiali Peng, Shuaiya Ma, Lifen Gao, Xiaohong Liang & Chunhong Ma

  2. School of Medicine, Shandong University, Jinan, Shandong, PR China

    Yuming Ding

  3. Center for Reproductive Medicine, School of Medicine, Cheeloo College of Medicine, Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Key Laboratory of Reproductive Endocrinology of the Ministry of Education, Shandong Provincial Clinical Medicine Research Center for Reproductive Health, Jinan, Shandong, PR China

    Tao Huang & Shigang Zhao

  4. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Histology and Embryology, School of Basic Medical Science, Shandong University, Jinan, Shandong, PR China

    Chunyang Li

  5. Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Shandong University, Jinan, Shandong, PR China

    Chunhong Ma

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  1. Chaojia Chen
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Contributions

C.C., C.L. and C.M. conceived the project and designed experiments; C.C. wrote the paper and performed experiments; C.L. and C.M. revised the manuscript and supervised the study; J.P., S.M., and Y.D. participated in the experiments; T.H., S.Z., L.G., and X.L. contributed to administrative, technical, or material support. All authors read and approved the final manuscript.

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Correspondence to Chunyang Li or Chunhong Ma.

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Chen, C., Peng, J., Ma, S. et al. Ribosomal protein S26 serves as a checkpoint of T-cell survival and homeostasis in a p53-dependent manner. Cell Mol Immunol 18, 1844–1846 (2021). https://doi.org/10.1038/s41423-021-00699-4

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