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

• DOI: 10.1126/scisignal.abi9983
• Publication Date: 2022-02-15T19:01:10Z
• Authors: Yongchao Liu; Yu Cong; Yujia Niu; Yin Yuan; Fancheng Tan; Qian Lai; Yanyan Hu; Bowen Hou; Jian Li; Chunjie Lin; Haiping Zheng; Junchen Dong; Jian Tang; Qinwei Chen; Joanna Brzostek; Xueqin Zhang; Xiao Lei Chen; Hong-Rui Wang; Nicholas R. J. Ga...; Bing Xu; Shu-Hai Lin; Guo Fu
• Keywords: Interleukin-15; 0301 basic medicine; Mice; 03 medical and health sciences; Receptors, Antigen, T-Cell; Animals; Intercellular Signaling Peptides and Proteins; Interleukin-2; Cell Differentiation; CD8-Positive T-Lymphocytes

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