Early Interferon Therapy for Hepatitis C Virus Infection Rescues Polyfunctional, Long-Lived CD8 ⁺ Memory T Cells

Abstract

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-␣) antiviral therapy achieves the highest rate of success when IFN-␣ is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCVspecific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-␥-and IL-2-producing and CD107a ؉ ) virus-specific CD8 ؉ T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8 ؉ T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-␣ rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.Hepatitis C virus (HCV) infection resolves spontaneously during the acute phase in a minority of infected individuals while the majority develop persistent viremia and chronic hepatitis over a period of years or decades (28). Understanding the immune response leading to spontaneous resolution during acute HCV infection has been hampered by the asymptomatic nature of the disease. Studies in the chimpanzee model and high-risk populations like intravenous drug users (IDUs) or healthcare workers following HCV exposure have demonstrated the absolute requirement for the CD8 ϩ and CD4 ϩ HCV-specific T-cell responses to prevent viral persistence (reviewed in reference 12 and 50). A cellular immune response is induced in most infected individuals, resulting in spontaneous resolution or transient control of viremia. However, this response is not sustained in individuals who develop viral persistence. The inefficiency of this initial immune response and viral recurrence in individuals who progress to chronic infection are likely due to the loss of CD4 ϩ T-cell help (16,20,56,57) and the rapid emergence of viral escape mutants in targeted CD8 ϩ cytotoxic T lymphocyte epitopes (9). Individuals who spontaneously resolve HCV infection develop long-lived memory Tcell responses (54) that can be protective upon reexposure (51). In contrast, cellular immune responses are mostly undetectable in the blood of persistently infected individuals and are ...

Dendritic Cell Inhibition Is Connected to Exhaustion of CD8+ T Cell Polyfunctionality during Chronic Hepatitis C Virus Infection

“…Functional exhaustion of an initially vigorous polyfunctional T cell response predicts the likelihood of viral persistence for HCV or HIV (20,29,30). It is generally viewed that the effects of such pathogens on T cell exhaustion are related largely to repeated Ag stimulation and the lack of CD4 help and PD-1/PD-L1 (or other) coinhibitory signals; however, their nonredundancy (31) implies that all of the factors involved in exhaustion are not defined.…”

“…How much more effective might interventions be if they were also taken to a level upstream of coinhibitory regulation of T cell function: at the level of those yet undefined pathways in DCs that are connected to preserved IL-2 secretion and CD107a mobilization by CD8 + T cells, despite chronic infection? Focused studies in this direction have the potential to provide the vaccine field with novel DC-based therapeutics to recover T cell polyfunctionality to tip the balance to immune control and clearance of virus once immune-suppressive signals are removed (e.g., PD-1) (29).…”

“…During chronic infections, PD-1/PD-L1 and an inadequate CD4 Th cell environment drive polyfunctional CD8 + T cells to exhaustion (20,29). Ex vivo HCV-specific CD4 responses were generally below the detection threshold of the assay, irrespective of grouping; when detected, there was no significant difference between CP clusters (p .…”

TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

“…The ability of secreting several cytokines is a common feature in polyfunctional effector T cells and it has also been correlated to a superior functional activity (5,(28)(29)(30). Because the murine Vb is not present on human T cells, we chose it as a marker for transduced T cells and analyzed the cytokine profile of the different TCR-transduced populations.…”

Functional Attributes of Responding T Cells in HCV Infection: The Recent Advances in Engineering Functional Antiviral T Cells

“…A rapid emergence of T helper responses in concert with CTL responses in the early disease often demonstrates a strong and persistent CTL response in resolving acute HCV infection. As for other viral infections, an efficient T cell response with poly-functionality has also been shown to correlate with resolution of HCV infection (Abdel-Hakeem et al 2010;Badr et al 2008;Ciuffreda et al 2008;Zimmerli et al 2005). According to the definition of antigen-experienced T cells (Sallusto et al 2004), the functional attributes of HCV-specific effector T cells in these patients resemble T cells that derive from the naïve and memory T cell (T CM : central memory, or T EM : effector memory) pools.…”