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

Abstract 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.