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Themis suppresses the effector function of CD8+ T cells in acute viral infection

Cellular & Molecular Immunology volume 20, pages 512–524 (2023)Cite this article

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Abstract

CD8+ T cells play a central role in antiviral immune responses. Upon infection, naive CD8+ T cells differentiate into effector cells to eliminate virus-infected cells, and some of these effector cells further differentiate into memory cells to provide long-term protection after infection is resolved. Although extensively investigated, the underlying mechanisms of CD8+ T-cell differentiation remain incompletely understood. Themis is a T-cell-specific protein that plays critical roles in T-cell development. Recent studies using Themis T-cell conditional knockout mice also demonstrated that Themis is required to promote mature CD8+ T-cell homeostasis, cytokine responsiveness, and antibacterial responses. In this study, we used LCMV Armstrong infection as a probe to explore the role of Themis in viral infection. We found that preexisting CD8+ T-cell homeostasis defects and cytokine hyporesponsiveness do not impair viral clearance in Themis T-cell conditional knockout mice. Further analyses showed that in the primary immune response, Themis deficiency promoted the differentiation of CD8+ effector cells and increased their TNF and IFNγ production. Moreover, Themis deficiency impaired memory precursor cell (MPEC) differentiation but promoted short-lived effector cell (SLEC) differentiation. Themis deficiency also enhanced effector cytokine production in memory CD8+ T cells while impairing central memory CD8+ T-cell formation. Mechanistically, we found that Themis mediates PD-1 expression and its signaling in effector CD8+ T cells, which explains the elevated cytokine production in these cells when Themis is disrupted.

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Data availability

For flow cytometry analysis, antibody-stained cells were run on an LSR-Fortessa X-20 analyzer (BD). All flow cytometry data were analyzed using FlowJo v.10.7.1 software (TreeStar). Statistical analysis was performed using GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA). GraphPad Prism was used for statistical analysis to compare outcomes using a two-tailed unpaired Student’s t test and two-tailed paired Student’s t test for cotransfer experiments; P  >  0.05 was considered not significant (ns); *P  ≤  0.05; **P  ≤  0.01; ***P  ≤  0.001 was considered statistically significant. All summarized data are shown in graphs with mean±sd.

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Acknowledgements

We would like to thank the Laboratory Animal Center, Xiamen University for help with mouse breeding and handling. We would like to thank the Core Facility of Biomedical Sciences, Xiamen University for Flow Cytometry Cell Sorting service. This study was supported by the National Natural Science Foundation of China (32070887) and the Fundamental Research Funds for the Central Universities (20720220003) to G.F. Singapore Ministry of Education (MOE-000112) and Singapore Ministry of Health’s National Medical Research Council (MOH-000523) to N.R.J. Gascoigne. The Natural Science Foundation of Fujian Province (No. 2019J01009) to Q.L. The National Natural Science Foundation of China (U1904206) to X.L.C. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. These authors contributed equally: Jian Tang, Xian Jia, Jian Li, Junchen Dong.

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China

    Jian Tang, Xian Jia, Jian Li, Junchen Dong, Jiayu Wang, Wanyun Li, Yuzhen Zhu, Yanyan Hu, Bowen Hou, Chunjie Lin, Yu Cong, Tong Ren, Changsheng Yan, Hongying Yang, Qian Lai, Haiping Zheng, Yuzhou Bao, Xiao Lei Chen, Qing Li & Guo Fu

  2. School of Life Sciences, Xiamen University, Xiamen, China

    Jian Tang, Xian Jia, Jian Li, Junchen Dong, Yuzhen Zhu, Yanyan Hu, Bowen Hou, Chunjie Lin & Hong-Rui Wang

  3. Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Namrata Gautam & Nicholas R. J. Gascoigne

  4. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Namrata Gautam & Nicholas R. J. Gascoigne

  5. Department of Hematology, The First Affiliated Hospital and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China

    Bing Xu & Guo Fu

  6. Cancer Research Center of Xiamen University, Xiamen, China

    Guo Fu

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Contributions

G.F., Q.L., and X.L.C. designed and supervised the study. J.T. X.J. J.L. and J.D. performed most experiments with help from others. C.L., W.L., and Q.L. provided critical reagents. N.R.J.G. and G.F. wrote the manuscript with input from all authors.

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Correspondence to Xiao Lei Chen, Qing Li, Nicholas R. J. Gascoigne or Guo Fu.

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Tang, J., Jia, X., Li, J. et al. Themis suppresses the effector function of CD8+ T cells in acute viral infection. Cell Mol Immunol 20, 512–524 (2023). https://doi.org/10.1038/s41423-023-00997-z

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