• 作者： I-Tsu Chyuan, Hsiu-Jung Liao, Tse-Hua Tan, Huai-Chia Chuang, Yu-Chuan Chu, Meng-Hsun Pan, Chien-Sheng Wu, Ching-Liang Chu, Bor-Ching Sheu & Ping-Ning Hsu
• 作者服務機構： 1.Department of Internal Medicine and Graduate Institute of Immunology, College of Medicine, National Taiwan University, 1 Jen-Ai Rd., Sec. 1, Taipei, 10051, Taiwan 2.Department of Internal Medicine, Cathay General Hospital, Taipei, 10630, Taiwan 3.Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City, Taipei, 22000, Taiwan 4.Department of Internal Medicine, National Taiwan University Hospital, Taipei, 10002, Taiwan 5.Department of Medical Research, Cathay General Hospital, Taipei, 10630, Taiwan 6.Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City, Taipei, 22000, Taiwan 7.Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University Hospital, National Taiwan University, Taipei, 10002, Taiwan 8.Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, 77030, USA 9.Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan 10.Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan 11.Immunology Research Center, National Health Research Institutes, Zhunan, 35053, Taiwan 12.Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan 13.School of Medicine, National Tsing Hua University, Hsinchu, 30013, Taiwan
• 中文摘要：
• 英文摘要：
  Background
  T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to induce cell death. Recent studies have indicated that TRAIL-R regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear. In this study, we screened for intracellular TRAIL-R-binding proteins within T cells to explore the novel signaling pathway transduced by TRAIL-R that directly inhibits T cell activation.
  
  Methods
  Whole-transcriptome RNA sequencing was used to identify gene expression signatures associated with TRAIL-R signaling during T cell activation. High-throughput screening with mass spectrometry was used to identify the novel TRAIL-R binding proteins within T cells. Co-immunoprecipitation, lipid raft isolation, and confocal microscopic analyses were conducted to verify the association between TRAIL-R and the identified binding proteins within T cells.
  
  Results
  TRAIL engagement downregulated gene signatures in TCR signaling pathways and profoundly suppressed phosphorylation of TCR proximal tyrosine kinases without inducing cell death. The tyrosine phosphatase SHP-1 was identified as the major TRAIL-R binding protein within T cells, using high throughput mass spectrometry-based proteomics analysis. Furthermore, Lck was co-immunoprecipitated with the TRAIL-R/SHP-1 complex in the activated T cells. TRAIL engagement profoundly inhibited phosphorylation of Lck (Y394) and suppressed the recruitment of Lck into lipid rafts in the activated T cells, leading to the interruption of proximal TCR signaling and subsequent T cell activation.
  
  Conclusions
  TRAIL-R associates with phosphatase SHP-1 and transduces a unique and distinct immune gatekeeper signal to repress TCR signaling and T cell activation via inactivating Lck. Thus, our results define TRAIL-R as a new class of immune checkpoint receptors for restraining T cell activation, and TRAIL-R/SHP-1 axis can serve as a potential therapeutic target for immune-mediated diseases.
• 中文關鍵字：
• 英文關鍵字： TRAIL receptor, Phosphatase, SHP-1, T cell receptor signaling