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SEL1L preserves CD8+ T-cell survival and homeostasis by fine-tuning PERK signaling and the IL-15 receptor-mediated mTORC1 axis

Cellular & Molecular Immunology volume 20, pages 1232–1250 (2023)Cite this article

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Abstract

SEL1L-mediated endoplasmic reticulum-associated degradation (ERAD) plays critical roles in controlling protein homeostasis by degrading misfolded or terminal unfolded proteins. However, it remains unclear how SEL1L regulates peripheral T-cell survival and homeostasis. Herein, we found that SEL1L deficiency led to a greatly reduced frequency and number of mature T cells, which was further validated by adoptive transfer experiments or bone marrow chimera experiments, accompanied by the induction of multiple forms of cell death. Furthermore, SEL1L deficiency selectively disrupted naïve CD8+ T-cell homeostasis, as indicated by the severe loss of the naïve T-cell subset but an increase in the memory T-cell subset. We also found that SEL1L deficiency fueled mTORC1/c-MYC activation and induced a metabolic shift, which was largely attributable to enhanced expression of the IL-15 receptor α and β chains. Mechanistically, single-cell transcriptomic profiling and biochemical analyses further revealed that Sel1l−/− CD8+ T cells harbored excessive ER stress, particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway, which was alleviated by supplementing IL-7 or IL-15. Importantly, PERK inhibition greatly resolved the survival defects of Sel1l−/− CD8+ T cells. In addition, IRE1α deficiency decreased mTORC1 signaling in Sel1l−/− naïve CD8+ T cells by downregulating the IL-15 receptor α chain. Altogether, these observations suggest that the ERAD adaptor molecule SEL1L acts as an important checkpoint for preserving the survival and homeostasis of peripheral T cells by regulating the PERK signaling cascade and IL-15 receptor-mediated mTORC1 axis.

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Acknowledgements

LZ was in part supported by the National Key R&D Program of China (2022YFA0807300), the National Natural Science Foundation of China (82271775 and 81971466), the Natural Science Foundation Outstanding Youth Fund of Jiangsu Province (BK20220049) and the CAMS Innovation Fund for Medical Sciences (CIFMS 2021-I2M-1-061, 2021-I2M-1-047 and 2022-I2M-2-004). BZ was in part supported by the Innovation Capability Support Program of Shaanxi 2021TD-38. JZ was in part supported by a Translational Research Grant of NCRCH (2020ZKZC04) and the National Natural Science Foundation of China (82071765). WL was supported by the Natural Science Foundation of China (NSFC 31900645). We thank Prof. Yonghong Wan from McMaster University, Canada, for his critical reading of the manuscript and helpful discussions.

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Author notes

  1. These authors contributed equally: Yafeng Gao, Wenhui Li, Zhenghao Wang, Cangang Zhang.

Authors and Affiliations

  1. National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China

    Yafeng Gao, Wenhui Li, Zhenghao Wang, Yaping He, Xiaowei Liu, Kexin Tang, Weiguo Zhang & Lianjun Zhang

  2. Key Laboratory of Synthetic Biology Regulatory Elements, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, 215123, Jiangsu, China

    Yafeng Gao, Wenhui Li, Zhenghao Wang, Yaping He, Xiaowei Liu, Kexin Tang & Lianjun Zhang

  3. School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China

    Zhenghao Wang

  4. Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi’an Jiaotong University, Xi’an, Shaanxi, China

    Cangang Zhang & Baojun Zhang

  5. Institute of Infection and Immunity, Translational Medicine Institute, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, China

    Cangang Zhang & Baojun Zhang

  6. Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, China

    Cangang Zhang & Baojun Zhang

  7. Xi’an Key Laboratory of Immune Related Diseases, Xi’an, Shaanxi, China

    Cangang Zhang & Baojun Zhang

  8. Department of Radiotherapy and Oncology, The Second Affiliated Hospital of Soochow University, Suzhou, China

    Yaping He

  9. Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, China

    Kexin Tang

  10. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cam-Su Mouse Genomic Resources Center, Medical College of Soochow University, Suzhou, Jiangsu, China

    Qiaoming Long

  11. Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, TaiKang Center for Life and Medical Sciences, The Institute for Advanced Studies, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China

    Yong Liu

  12. Institute of Biology and Medical Sciences (IBMS), Soochow University, Suzhou, 215123, Jiangsu, China

    Jinping Zhang

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  1. Yafeng Gao
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Contributions

LZ and YG conceived the experiments; LZ, BZ and JZ designed the experiments; and YG, WL and ZW performed most of the experiments. CZ performed bioinformatics analysis of the single-cell RNA-seq data. YH, KT and XL helped maintain the mouse line and perform PCR analysis. WZ, QL and YL helped with data interpretation and valuable discussions. LZ, YG and WL wrote the manuscript. All authors provided intellectual input to the manuscript.

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Correspondence to Jinping Zhang, Baojun Zhang or Lianjun Zhang.

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Gao, Y., Li, W., Wang, Z. et al. SEL1L preserves CD8+ T-cell survival and homeostasis by fine-tuning PERK signaling and the IL-15 receptor-mediated mTORC1 axis. Cell Mol Immunol 20, 1232–1250 (2023). https://doi.org/10.1038/s41423-023-01078-x

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