CD8+ T cells recognising their cognate antigen are typically recruited as a polyclonal population consisting of multiple clonotypes with varying T-cell receptor (TCR) affinity to the target peptide-MHC (pMHC) complex. Advances in single-cell sequencing have increased accessibility towards identifying TCRs with matched antigens. Here we present the discovery of a monoclonal CD8+ T cell population with specificity for a hepatitis C virus (HCV)-derived HLA class I epitope (HLA-B*07:02 GPRLGVRAT) which was isolated directly ex vivo from an individual with an episode of acutely resolved HCV infection. This population was absent prior to infection and underwent expansion and stable maintenance for at least two years after infection as measured by HLA-multimer staining. Furthermore, the monoclonal clonotype was characterised by an unusually long dissociation time (half-life = 794 seconds and koff = 5.73×10-4) for its target antigen when compared to previously published results. A comparison with related populations of HCV-specific populations derived from the same individual and a second individual suggest that high-affinity TCR-pMHC interactions may be inherent to epitope identity and shape the phenotype of responses which has implications for rational TCR selection and design in the age of personalised immunotherapies.

Early neutralising antibodies against Hepatitis C virus (HCV) and CD8+T cell effector responses can lead to viral clearance. However, these functions alone are not sufficient to protect patients against HCV infection, thus yet undefined additional anti-viral immune mechanisms are required. In recent years, Fc-receptor-dependent antibody effector functions particularly, antibody-dependent cellular phagocytosis (ADCP) was shown to offer immune protection against several RNA viruses. However, its development, and clinical role in patients with HCV infection remain unknown. In this study, we found that patients with chronic GT1a or GT3a HCV infection had significantly higher concentrations of anti-envelop 2 (E2) antibodies, predominantly IgG1 subclass, than patients that cleared the viruses while the latter had antibodies with higher affinities. 97% of the patients with HCV had measurable ADCP of whom patients with chronic disease showed significantly higher ADCP than those who naturally cleared the virus. Epitope mapping studies showed that patients with antibodies that target antigenic domains on the HCV E2 protein that are known to associate with neutralisation function also strongly associated with ADCP, suggesting antibodies with overlapping/dual functions. Correlation studies showed that ADCP significantly correlated with plasma anti-E2 antibody levels and neutralisation function regardless of clinical outcome and genotype of infecting virus while a significant correlation between ADCP and affinity was only evident in patients that cleared the virus. These results suggest ADCP was mostly driven by antibody titre in patients with chronic disease while maintained in clearers due the quality (affinity) of their anti-E2 antibodies despite having lower antibody titres.