Factors that Determine the Antiviral Efficacy of HCV-Specific CD8+ T cells Ex Vivo
2013
Authors: Seigel B, Bengsch B, Lohmann V, Bartenschlager R, Blum HE, Thimme R
CellNetworks People: Bartenschlager Ralf, Lohmann Volker
Journal: Gastroenterology.

BACKGROUND & AIMS:: Dysfunctional CD8+ T cells are believed to contribute to the ability of hepatitis C virus (HCV) to evade the immune response. Most studies have focused on the effector functions of HCV-specific CD8+ T cells or their surface expression of inhibitory receptors. There is currently no information available about the ex vivo ability of HCV-specific CD8+ T cells to inhibit viral replication (antiviral efficacy). METHODS:: To analyze the antiviral efficacy of virus-specific CD8+ T cells ex vivo we utilized an immunological model based on a cell line that expresses HLA-A*02 and contains a stably replicating HCV reporter replicon. We isolated HCV-specific CD8+ T cells from 18 HLA-A*02-positive patients with chronic HCV infection and 15 subjects that resolved HCV infection (7 spontaneous, 8 after therapy). Replicon cells were labeled with virus-specific peptides; inhibition of HCV replication was determined by measuring luciferase activity after 72 hours co-culture with virus-specific CD8+ T cells. RESULTS:: HCV-specific CD8+ T cells from patients with chronic HCV infection had a significantly lower antiviral efficacy than influenza-, Epstein-Barr virus-, and cytomegalovirus-specific CD8+ T cells. Antiviral efficacy was associated with the ability of virus-specific CD8+ T cells to secrete interferon (IFN)-γ. Antiviral efficacy of HCV-specific CD8+ T cells was linked to surface expression of CD127 and PD-1. The cytokines interleukin (IL)-2, IL-7, and IL-15 increased the antiviral efficacy of CD127-positive, but not of CD127-negative, HCV-specific CD8+ T cells. Spontaneous, but not antiviral therapy-induced, viral clearance was associated with increased antiviral efficacy. CONCLUSION:: The ability of CD8+ T cells to inhibit HCV replication ex vivo is associated with their ability to secrete IFN-γ and their surface expression of CD127 and PD-1.