CD8 + T Cell Cytotoxicity and Exhaustion Underlie Liver Allograft Rejection: Insights From a Murine Transcriptomic Atlas

ABSTRACT The gene expression uncovering the molecular mechanism of liver transplantation (LT) rejection and immune tolerance remains unclear. The mice orthotopic LT rejection and tolerance models were established. Liver sections were obtained for transcriptome sequencing. A total of 2560 DEGs were identified in the rejection group. The major enrichment pathways included graft‐versus‐host disease, Th17 cell differentiation, T cell receptor signaling pathway and cytokine‐cytokine receptor interaction. The screened top 10 hub genes, including Ctla4, Ifng, Gzmb, Pdcd1, cd28, cd8a, Tbx21, and Lag3 , were associated with T cell cytotoxicity and exhaustion. The gene expression levels of functional characteristics of T cell exhaustion, including Il2ra, Tnf, and Ifng were all significantly decreased in the tolerance group. Flow cytometry confirmed the significantly higher expression of TIM‐3 and PD‐1 in CD8 + T cells. Immunohistochemical staining of liver tissues also showed remarkably increased granzyme‐B‐positive cells in the rejection group. A comprehensive molecular profiling of the immune alterations was observed, especially the dynamic change of CD8 + T cell‐mediated cytotoxicity and exhaustion. This provides new insights into the molecular mechanism of LT rejection and immune tolerance.