Functional suppression by FoxP3⁺CD4⁺CD25 ^high regulatory T cells during acute hepatitis C virus infection

Background. Infection with hepatitis C virus (HCV) is characterized by impairment of viral effector T cell responses and a high propensity for viral persistence. Previous studies have demonstrated that chronic HCV infection is associated with an increased frequency of regulatory T (T_reg) cells, compared with that in persons whose infection resolved and in healthy persons. However, all patients in prior analyses had exposures in the distant past, precluding the ability to determine whether T_reg cells play a causal role in establishing persistence during the earliest stages of infection or whether they are expanded because of viral persistence. Methods. For the first time, we longitudinally analyzed T_reg cells in patients with acute HCV infection (n = 27). We used a multiparameter approach, including fluorescence-activated cell sorting analysis of cell-surface and intracellular antigens, coculture experiments with highly purified CD4⁺CD25 ^high regulatory and CD4⁺CD25^- responder cell populations, and multiplex analysis of secreted cytokines. Results. Forkhead transcription factor 3 (FoxP3) expression and T_reg cell suppression were greater in patients with acute HCV infection than in healthy control subjects but were not different at the first time point among patients who subsequently developed persistence or resolved HCV infection spontaneously; however, 6 months later, the resolution of disease was associated with a relative loss of functional suppression. Conclusions. Collectively, these data indicate that patients with acute HCV infection who develop chronicity versus spontaneous resolution exhibit temporal changes in T_reg cell function. It is possible that repetitive viral antigenic stimulation alters the function of T_reg cells over time.