Epithelial Galectin-3 Induced the Mitochondrial Complex Inhibition and Cell Cycle Arrest of CD8+ T Cells in Severe/Critical COVID-19

作者：Wang, Yudie; Yang, Cheng; Wang, Zhongyi; Wang, Yi; Yan, Qing; Feng, Ying; Liu, Yanping; Huang, Juan^*; Zhou, Jingjiao^*

来源：INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2023, 24(16): 12780.

DOI：10.3390/ijms241612780

• COVID-19
• CD8(+) T cell
• cell cycle arrest
• mitochondrial complex genes
• galectin-3

Previous research suggested that the dramatical decrease in CD8(+) T cells is a contributing factor in the poor prognosis and disease progression of COVID-19 patients. However, the underlying mechanisms are not fully understood. In this study, we conducted Single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) analysis, which revealed a proliferative-exhausted MCM(+)FASLG(low) CD8(+) T cell phenotype in severe/critical COVID-19 patients. These CD8+ T cells were characterized by G2/M cell cycle arrest, downregulation of respiratory chain complex genes, and inhibition of mitochondrial biogenesis. CellChat analysis of infected lung epithelial cells and CD8(+) T cells found that the galectin signaling pathway played a crucial role in CD8(+) T cell reduction and dysfunction. To further elucidate the mechanisms, we established SARS-CoV-2 ORF3a-transfected A549 cells, and co-cultured them with CD8(+) T cells for ex vivo experiments. Our results showed that epithelial galectin-3 inhibited the transcription of the mitochondrial respiratory chain complex III/IV genes of CD8+ T cells by suppressing the nuclear translocation of nuclear respiratory factor 1 (NRF1). Further findings showed that the suppression of NRF1 translocation was associated with ERK-related and Akt-related signaling pathways. Importantly, the galectin-3 inhibitor, TD-139, promoted nuclear translocation of NRF1, thus enhancing the expression of the mitochondrial respiratory chain complex III/IV genes and the mitochondrial biogenesis of CD8(+) T cells. Our study provided new insights into the immunopathogenesis of COVID-19 and identified potential therapeutic targets for the prevention and treatment of severe/critical COVID-19 patients.

• 单位
  华中科技大学