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TRAF2 regulates T cell immunity by maintaining a Tpl2-ERK survival signaling axis in effector and memory CD8 T cells

Cellular & Molecular Immunology volume 18, pages 2262–2274 (2021)Cite this article

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Abstract

Generation and maintenance of antigen-specific effector and memory T cells are central events in immune responses against infections. We show that TNF receptor-associated factor 2 (TRAF2) maintains a survival signaling axis in effector and memory CD8 T cells required for immune responses against infections. This signaling axis involves activation of Tpl2 and its downstream kinase ERK by NF-κB-inducing kinase (NIK) and degradation of the proapoptotic factor Bim. NIK mediates Tpl2 activation by stimulating the phosphorylation and degradation of the Tpl2 inhibitor p105. Interestingly, while NIK is required for Tpl2-ERK signaling under normal conditions, uncontrolled NIK activation due to loss of its negative regulator, TRAF2, causes constitutive degradation of p105 and Tpl2, leading to severe defects in ERK activation and effector/memory CD8 T cell survival. Thus, TRAF2 controls a previously unappreciated signaling axis mediating effector/memory CD8 T cell survival and protective immunity.

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Acknowledgements

We thank R Brink for the Traf2-flox mice, Genentech Inc. for the Map3k14 flox mice and R Starr for the Nfkb2lym1 mice. We also thank the personnel from the flow cytometry, DNA analysis, and animal facilities at The MD Anderson Cancer Center for technical assistance. This study was supported by grants from the National Institutes of Health (AI64639 and GM84459), and the core facilities of MD Anderson Cancer Center are supported by the NIH/NCI Cancer Center Support Grant (CCSG) P30CA016672.

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Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX, 77030, USA

    Xiaoping Xie, Lele Zhu, Zuliang Jie, Yanchuan Li, Meidi Gu, Xiaofei Zhou, Hui Wang, Jae-Hoon Chang, Chun-Jung Ko, Xuhong Cheng & Shao-Cong Sun

  2. Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China

    Hui Wang

  3. College of Pharmacy, Yeungnam University, Gyeongsan, 712-749, Republic of Korea

    Jae-Hoon Chang

  4. MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences, Houston, TX, 77030, USA

    Shao-Cong Sun

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Contributions

X.X. designed and performed the research, prepared the figures, and wrote part of the manuscript; L.Z., Z.J., Y.L., M.G., X.Z., H.W., J.H.C., C.J.K., and X.C. contributed to performing the experiments; and S-C.S. supervised the work and wrote the manuscript.

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Correspondence to Shao-Cong Sun.

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Xie, X., Zhu, L., Jie, Z. et al. TRAF2 regulates T cell immunity by maintaining a Tpl2-ERK survival signaling axis in effector and memory CD8 T cells. Cell Mol Immunol 18, 2262–2274 (2021). https://doi.org/10.1038/s41423-020-00583-7

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