IL-15-induced CD38+HLA-DR+CD8+ T cells correlate with liver injury via NKG2D in chronic hepatitis B cirrhosis

Abstract

Objectives

CD8⁺ T cells play a critical role in the immune dysfunction associated with liver cirrhosis. CD38⁺HLA-DR⁺CD8⁺ T cells, or bystander-activated CD8⁺ T cells, are involved in tissue injury but their specific contribution to liver cirrhosis remains unclear. This study sought to identify the mechanism for CD38⁺HLA-DR⁺CD8⁺ T cell-mediated pathogenesis during liver cirrhosis.

Methods

The immunophenotype, antigen specificity, cytokine secretion and cytotoxicity-related indicators of CD38⁺HLA-DR⁺CD8⁺ T cells were determined using flow cytometry. The functional properties of these cells were assessed using transcriptome analysis. CD38⁺HLA-DR⁺CD8⁺ T-cell killing was detected using cytotoxicity and antibody-blocking assays.

Results

The proportion of CD38⁺HLA-DR⁺CD8⁺ T cells was significantly elevated in liver cirrhosis patients and correlated with tissue damage. Transcriptome analysis revealed that these cells had innate-like functional characteristics. This CD8⁺ T-cell population primarily consisted of effector memory T cells and produced a high level of cytotoxicity-related cytokines, granzyme B and perforin. IL-15 promoted CD38⁺HLA-DR⁺CD8⁺ T-cell activation and proliferation, inducing significant TCR-independent cytotoxicity mediated through NKG2D.

Conclusions

CD38⁺HLA-DR⁺CD8⁺ T cells correlated with cirrhosis-related liver injury and contributed to liver damage by signalling through NKG2D in a TCR-independent manner.