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-gamma 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.