Multi-functional HCV-specific CD4+ T cells associated with viral control during the postpartum period express Th1- and Tfh-biasing transcription factors

Abstract

Abstract Chronic hepatitis C virus (HCV) infection is characterized by dysfunctional HCV-specific CD8+ T cells, rare CD4+ T responses, and stable high-level viremia. Recovered CD4+ T cell function and unusual declines in viremia have been observed in some women after childbirth. Whether recovered CD4+ T cells are of lineages to help B cells or CD8 T cells is unknown. Preliminary studies suggest both may be true. In 7 women with postpartum viral suppression (>= 1 log10 by 3 months postpartum, “controllers”), and 7 women with more stable viral levels, “non-controllers”, circulating HCV-tetramer+ (tet+) CD4+ T cells expressed chemokine receptors associated with two predominate populations, Th1-biased Tfh (cTfh1) cells and Th1 cells – with a higher cTfh1/Th1 ratio linked to viral control. Here we assessed HCV-specific cTfh1 and Th1 functional responses by combined surface chemokine receptor and intracellular cytokine staining (ICS) after HCV peptide stimulation, and we also assessed expression of lineage-defining transcription factors on HCV-tet+ cells. HCV-specific cytokine+ cells were predominantly cTfh1 or Th1 populations, and multi-functionality correlated with viral control. HCV-tet+ CD4+ T cell Tbet and BCL6 expression levels did not differ by degree of viral control, but both were enhanced in tet+cTfh1 cells relative to bulk cTfh1 cells, and tet+ Th1 cells expressed significantly more BCL6 than bulk Th1 cells. Together, these data point to a postpartum CD4+ T cell recovery driven by transcription factors favoring cTfh1/Th1-biased phenotypes. Understanding how these cells interact with CD8+ T cells and B cell will be vital for understanding this unique instance of natural control of a chronic viral infection. Supported by a grant from the NIH (R01 AI096882).