Innate-like bystander-activated CD38⁺HLA-DR⁺CD8⁺T cells play a pathogenic role in patients with chronic hepatitis C

Background and Aims: HCV-specific T cells are few and exhausted in patients with chronic hepatitis C (CHC). Whether these T cells are responsible for the liver damage and fibrosis is still debated. However, cluster of differentiation 38–positive (CD38⁺) human leukocyte antigen DR–positive (HLA-DR⁺) CD8⁺ T cells are regarded as bystander CD8⁺ T cells that cause liver injury in acute hepatitis. We propose that these innate CD8⁺ T cells play a pathogenic role in CHC. Methods: Lymphocytes from peripheral blood were obtained from 108 patients with CHC and 43 healthy subjects. Immunophenotyping, functional assays, T-cell receptor (TCR) repertoire, and cytotoxic assay of CD38⁺HLA-DR⁺CD8⁺ T cells were studied. Results: The percentage of CD38⁺HLA-DR⁺CD8⁺ T cells increased significantly in patients with CHC. These cells expressed higher levels of effector memory and proinflammatory chemokine molecules and showed higher interferon-γ production than CD38⁻HLA-DR⁻ CD8 T cells. They were largely composed of non-HCV-specific CD8⁺ T cells as assessed by HLA-A2-restricted pentamers and next-generation sequencing analysis of the TCR repertoire. In addition, these CD38⁺HLA-DR⁺CD8⁺ T cells had strong cytotoxicity, which could be inhibited by anti–DNAX accessory molecule 1, anti–NKG2 family member D, and anti–natural killer NKp30 antibodies. Lastly, the percentage of CD38⁺HLA-DR⁺CD8⁺ T cells was significantly associated with liver injury and fibrosis and decreased significantly along with serum alanine aminotransferase normalization after successful direct-acting antiviral treatment. Conclusions: The TCR-independent, cytokine-responsive bystander CD38⁺HLA-DR⁺CD8⁺ T cells are strongly cytotoxic and play a pathogenic role in patients with CHC.