TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation

Differentiation and fate of virus-specific CD8(+) T cells after cessation of chronic antigen stimulation is unclear. Here we show that a TCF1(+)CD127(+)PD1(+) hepatitis C virus (HCV)-specific CD8(+) T-cell subset exists in chronically infected patients with phenotypic features of T-cell exhaustion and memory, both before and after treatment with direct acting antiviral (DAA) agents. This subset is maintained during, and for a long duration after, HCV elimination. After antigen re-challenge the less differentiated TCF1(+)CD127(+)PD1(+) population expands, which is accompanied by emergence of terminally exhausted TCF1-CD127-PD1(hi) HCV-specific CD8(+) T cells. These results suggest the TCF1(+)CD127(+)PD1(+) HCV-specific CD8(+) T-cell subset has memory-like characteristics, including antigen-independent survival and recall proliferation. We thus provide evidence for the establishment of memory-like virus-specific CD8(+) T cells in a clinically relevant setting of chronic viral infection and we uncover their fate after cessation of chronic antigen stimulation, implicating a potential strategy for antiviral immunotherapy.