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- PD1hi HCV-specific CD8⁺ T cells. These results suggest the TCF1⁺CD127⁺PD1⁺ HCVspecific 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.