Exhaustion of intra-hepatic CD8+ T cells targeting intact and escaped MHC class I epitopes in chronic phase of hepatitis C virus infection (39.20)

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Abstract Hepatitis C virus (HCV)-specific CD8+ T cells persist in the chronically infected liver but provide no apparent control of virus replication. Epitopes targeted by some of these T cells contain escape mutations while others remain intact. Studies in acutely infected humans suggest that circulating CD8+ T cells targeting the intact epitopes express more PD-1, a molecule associated with loss of effector function. Whether this is true in the persistently infected liver is unknown. CD8+ T cells targeting intact or mutated epitopes were visualized using tetramers in the liver of chronically infected chimpanzees. Unexpectedly, there was no obvious relationship between expression of PD-1 on the HCV-specific CD8+ T cells and the nature of the targeted epitope. More importantly all HCV-specific CD8+ T cells we examined displayed functional incapacity regardless of the nature of the targeted epitope and anergy could not be reversed by blockade of the PD-1/PD-L1 pathway. We conclude that decreased PD-1 expression previously observed on acute phase CD8+ T cells after escape of the targeted epitope is not necessarily maintained in the liver during chronic hepatitis C. Rather, our data suggest that mechanisms other than continuous TCR triggering might be responsible for PD-1 upregulation and exhaustion of CD8+ T cells, or that escaped epitopes are still able to induce TCR engagement without T cell activation resulting in exhaustion of viral specific CD8+ T cells.

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