A follicular T helper cell axis sustains antiviral CD4+T cell immunity in chronic infection in humans

Virus-specific CD4+T cells are key orchestrators of adaptive immunity, yet their differentiation trajectories and long-term maintenance during chronic infection remain incompletely defined. Using human hepatitis C virus (HCV) as a model, we investigated how infection outcomes shape virus-specific CD4+T cell fates. We longitudinally analyzed HCV-specific CD4+T cells from individuals across acute, acute-resolved, chronic, and direct-acting antiviral (DAA) therapy cured infection states. MHC class II tetramer-based enrichment enabled characterization of virus-specific CD4+T cells phenotypically, transcriptionally and functionally using high-dimensional flow cytometry, single-cell RNA and TCR sequencing, and PMA-ionomycin stimulation assays, respectively. In chronic infection, a population of stem-like TCF-1+Bcl-2+CD4+T cells with T follicular helper (Tfh)-biased features gave rise to T-bet+Th1-like effector cells. Shared TCR clonotypes between these subsets and trajectory analysis supported a linear differentiation hierarchy. Functionally, CD4+T cells from chronic infection exhibited diminished cytokine secretion compared to acute-resolving infection. Following HCV cure, stem-like CD4+T cells persisted as a stable memory pool for up to eight years but retained transcriptional imprints of chronic infection. In conclusion, CD4+T cell responses in chronic infection are sustained by a stem-like subset that gives rise to effector cells and persists long term after HCV cure. These cells retain transcriptional features of chronic antigen exposure, a chronic scar, in contrast to bona fide memory cells obtained after acute-resolved infection. These results reveal similarities in the differentiation of CD4+and exhausted CD8+T cells with implications beyond chronic HCV infection. Publication History Article published online: 26 January 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany