A liver-infiltrating CD4+ Tfh1 cell response predicts HCV control, hepatitis, and seroconversion during acute infection

Sustained CD4+ T cell immunity is required for resolution of acute hepatitis C virus (HCV) infection but the response remains poorly characterized. Here, circulating CD4+ T cells with high PD-1 and ICOS co-expression were temporally associated with onset of virus control, seroconversion, and hepatitis in HCV-infected chimpanzees. Co-production of Tfh (IL-21, CXCL13) and Th1 (IFN-γ, TNF) cytokines after stimulation with HCV non-structural proteins demonstrated that the response was predominately Tfh1-like and virus-specific. Transcriptional analysis confirmed a Tfh1 lineage assignment. Effector-related genes such as ADGRG1 (GPR56), ZNF683 (Hobit), and KLRB1 (CD161) were also expressed. HCV-specific PD-1hiICOShi CD4+ Tfh1-like cells were enriched in liver, suggesting the potential for B and CD8+ T cell help at the site of virus replication. Most circulating and intrahepatic PD-1hiICOShi CD4+ Tfh1-like cells did not express CXCR5, and therefore resembled CXCR5-negative CXCL13-positive peripheral helper (Tph) cells that infiltrate tumors and tissues inflamed by autoimmunity. PD-1hiICOShi CD4+ cells also peaked after hepatitis A virus infection, but the response was accelerated by several weeks when compared with HCV infection. The PD-1hiICOShi phenotype, and temporal association between the peak response and ALT, may provide markers to guide human studies of CD4+ T cell immunity against HCV and other hepatotropic viruses.