CD38+HLA-DR+CD8+ T Cells induced by IL-15 exert liver injury through NKG2D in chronic hepatitis B cirrhosis

Abstract

Abstract Background: Liver cirrhosis could lead to immune dysfunction. During the pathogenesis of liver cirrhosis, CD8+ T cells play a critical role. While CD38+HLA-DR+CD8+ T cells, also called bystander activation CD8+ T cells, had been shown to be involved in host injury, its specific contribution to liver cirrhosis had remained not unclear. The aim of this study was to understand how these CD38+HLA-DR+CD8+ T cells exerted a pathogenic role in liver cirrhosis. Methods: Flow cytometry was performed to detect the immunophenotype, antigen-specific T cells, cytokines secretion, and cytotoxicity related indicators of CD38+HLA-DR+CD8+ T cells. Transcriptome analysis was utilized to analyze the functional properties of these cells. The cytotoxicity of CD38+HLA-DR+CD8+ T cells was detected by cytotoxicity assay and antibody blocking assay. Results: The percentage of CD38+HLA-DR+CD8+ T cells in patients with liver cirrhosis significantly increased and was correlated with liver injury. These CD8+ T cells contained largely non-HBV specific T cells. Transcriptome analysis revealed that these CD8+ T cells subsets exhibited innate-like functional characteristic. In addition, these cells mainly consisted of effector memory T cells and displayed high expression levels of cytotoxicity-related cytokines, especially granzyme B and perforin. Stimulation experiments with cytokines shown that IL-15 could promote the activation and proliferation of these CD8+ T cells. Lastly, blocking assays indicated that CD38+HLA-DR+CD8+ T cells had strong cytotoxic effects in a TCR-independent manner, mediated by NKG2D. Conclusion: CD38+HLA-DR+CD8+ T cells were correlated with the liver injury in liver cirrhosis, and these cells exerted liver damaging effects through NKG2D in a TCR-independent manner.