Hepatitis C virus (HCV)-specific CD8 T-cells in HCV-seronegative individuals: Frequency and T-cell receptor repertoire (TCR)

Memory CD8 T-cells cross-reactive with a heterologous virus have shown to provide either protective immunity and/or immune pathology. In humans, proliferation of cross-reactive CD8 memory T-cells has been implicated in infectious mononucleosis (IM) and subfulminant acute HCV-infection. Since each individual has its own private immune repertoire, the frequency of memory T cells polyspecific to HCV can vary and the specificity is determined by the CDR3 of the TCR. This study aimed to determine the frequency and TCR of HCV-specific CD8 T-cells in HCV-seronegative individuals with different risk profiles for HCV transmission. 60 HCV-seronegative HLA-A2+ individuals were studied (14 risk free, 19 unknown blood donors, 15 sexual partners of HCV patients, 7 health care worker, 5 iv drug user). HCV-NS3(1073)-specific T-cell lines were generated. Response was defined based on proliferation by CFSE and tetramer frequency. TCR-analysis of tetramer-sorted cells was performed by RT-PCR with Vb-specific primer and subcloning/sequencing of CDR3. TCR of HCV-seronegative responder was compared with TCR used in acute HCV-infection. In 18/60 individuals, HCV-NS3(1073)-specific cells proliferated and variable frequencies (0,4–76%) of tetramer+ cells were documented independent from the risk group. TCR-analysis of the highly responding individual (risk free group) showed usage of only TCR-Vb6.2 (oligoclonal response). Interestingly, the CDR3 of the dominant clone (Vb6.2-QEAGAP-Jb2.2) revealed the presence of similar amino acids found in patients with acute HCV-infection (Vb6.2-LxGxP-Jb 2.7, Vb6.2-ExAxG-Jb 2.3). The TCR of low responding individuals were more diverse. Our study confirmed that HCV-NS3(1073)-specific CD8 T-cells exist in HCV-seronegative individuals. The variability between individuals is consistent with the concept of private specificity. The pattern of TCR usage was also reminiscent to previously identified cross-reactive responses in mouse models or during IM.

CD8 T cells - Hepatitis C - T cell receptor repertoire - private specificity