Virus-Specific CD4+ T Cells Have Functional and Phenotypic Characteristics of Follicular T-Helper Cells in Patients With Acute and Chronic HCV Infections

Background & Aims Follicular T-helper (Tfh) cells contribute to pathogen-specific antibody responses by providing maturation signals to B cells. In mice with viral infections, virus-specific Tfh cells expand and are required to contain the infection. However, less is known about human virus–specific Tfh cells or their functions during infection. We investigated whether virus-specific CD4+ T cells from patients with hepatitis C virus (HCV) infection had phenotypic or functional features of Tfh cells and contribute to the production of HCV-specific antibodies. Methods We collected blood samples from patients with acute and chronic HCV infection and healthy individuals (controls). We performed MHC class II tetramer analyses, assays to detect intracellular cytokines in response to HCV exposure, and analyses to quantify HCV-specific antibodies. In addition, we collected liver tissues from patients with chronic HCV infection or nonviral liver disease to analyze markers of Tfh cells. Results HCV-specific CD4+ T cells from patients with acute HCV infection expressed markers of Tfh cells and secreted interleukin 21 in response to HCV exposure. Longitudinal analyses of HCV-specific T-cell responses and antibody responses showed an association between expression of inducible T-cell co-stimulator and induction of virus-specific antibodies in patients with acute HCV infection. Markers of Tfh cells were barely detectable in the peripheral blood samples from patients with chronic HCV infection, but were detected in liver tissues. Conclusions Virus-specific Tfh cells can be detected in blood samples from patients with acute HCV infection; inducible T-cell co-stimulator expression correlates with production of HCV-specific antibodies. In patients with chronic infection, Tfh cells seem to disappear from the blood but are detectable in the liver.