Characterization of hepatitis C virus-specific Th1 and Th1-biased circulating T follicular helper CD4+ T cells that arise following pregnancy

Abstract

Abstract Chronic hepatitis C virus (HCV) infection is marked by a loss of HCV-specific CD4+ T cells and CD8+ T cell exhaustion. However, recovery of antiviral CD4+ T cells and decreased viremia occurs in some women after pregnancy. We hypothesize that recovery of HCV-specific Th1 and Tfh biased CD4+ T cell populations contributes to viral control postpartum. Here we undertook a detailed phenotypic analysis of lineage-defining chemokine receptor expression on recovering HCV-specific CD4+ T cells using tetramer staining and flow cytometry of PBMCs from 14 women with chronic HCV infection. Seven women had >10-fold decreases in viremia by 3 months postpartum (3PP) (controllers) and the remaining half did not (non-controllers). At 3PP, tetramer+CD4+T cells were predominantly CXCR5+/CXCR3+/CCR6− (cTfh1) with most of the remaining HCV-specific CD4+ T cells being CXCR5−/CXCR3+/CCR6−(Th1). The proportions of cTfh1 cells within tetramer+CD4+ T cell populations were higher in controllers compared to non-controllers (median 74.3% vs. 52.8%, p=0.0262, Mann-Whitney), while the proportions of Th1 cells were higher in non-controllers (p=0.007, Mann-Whitney). Higher cTfh1 frequencies correlated with viral control (p=0.0072, Spearman). In all mothers, over 85% of HCV-specific cTfh1 cells were PD-1+. ICOS expression correlated with reduced viral control. Together, these data suggest that a shift of HCV-specific CD4+ T cell responses towards a cTfh1 phenotype contributes to the unique viral control that occurs in some women after pregnancy.