2. Academic Validation
  3. Themis is indispensable for IL-2 and IL-15 signaling in T cells

Themis is indispensable for IL-2 and IL-15 signaling in T cells

  • Sci Signal. 2022 Feb 15;15(721):eabi9983. doi: 10.1126/scisignal.abi9983.
Yongchao Liu 1,  Yu Cong 2 3,  Yujia Niu 1,  Yin Yuan 1,  Fancheng Tan 1,  Qian Lai 2,  Yanyan Hu 1,  Bowen Hou 1,  Jian Li 1,  Chunjie Lin 1,  Haiping Zheng 2,  Junchen Dong 1,  Jian Tang 1,  Qinwei Chen 2,  Joanna Brzostek 4 5,  Xueqin Zhang 6,  Xiao Lei Chen 2,  Hong-Rui Wang 1 6,  Nicholas R J Gascoigne 4 5,  Bing Xu 2 7,  Shu-Hai Lin 1,  Guo Fu 1 2 3 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, China.
  • 2 Department of Hematology, First Affiliated Hospital and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, China.
  • 3 Cancer Research Center of Xiamen University, Xiamen, China.
  • 4 Immunology Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 5 Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 6 Department of Obstetrics and Gynecology, Affiliated Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
  • 7 Key Laboratory of Xiamen for Diagnosis and Treatment of Hematological Malignancy, Xiamen, China.
PMID: 35167340 DOI: 10.1126/scisignal.abi9983
Abstract

To perform their Antiviral and antitumor functions, T cells must integrate signals both from the T cell receptor (TCR), which instruct the cell to remain quiescent or become activated, and from cytokines that guide cellular proliferation and differentiation. In mature CD8+ T cells, Themis has been implicated in integrating TCR and cytokine signals. We investigated whether Themis plays a direct role in cytokine signaling in mature T cells. Themis was required for IL-2- and IL-15-driven CD8+ T cell proliferation both in mice and in vitro. Mechanistically, we found that Themis promoted the activation of the transcription factor STAT and mechanistic target of rapamycin signaling downstream of Cytokine Receptors. Metabolomics and stable isotope tracing analyses revealed that Themis deficiency reduced glycolysis and serine and nucleotide biosynthesis, demonstrating a receptor-proximal requirement for Themis in triggering the metabolic changes that enable T cell proliferation. The cellular, metabolic, and biochemical defects caused by Themis deficiency were corrected in mice lacking both Themis and the Phosphatase Shp1, suggesting that Themis mediates IL-2 and IL-15 receptor-proximal signaling by restraining the activity of Shp1. Together, these results not only shed LIGHT on the mechanisms of cytokine signaling but also provide new clues on manipulating T cells for clinical applications.

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