Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection

Abstract

ObjectiveChronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control.DesignThe phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection.ResultsWe detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities.ConclusionHBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure.

Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

“…Similar findings were observed for HBV‐specific T cells that downregulated their PD‐1 expression following disease resolution . These observations were in line with differential expression of PD‐1 on LCMV‐specific T cells in acute and chronic LCMV‐infected mice .…”

“…During acute LCMV infection in mice, PD‐1 was transiently expressed on LCMV‐specific CD8 + T cells and subsequently downregulated . Correspondingly, circulating HBV‐ and HCV‐specific CD8 + T cells highly expressed PD‐1 at the acute stage of infection . In acute HBV, envelope‐specific T cells expressed the highest levels of PD‐1 compared with virus‐specific T cells targeting core and polymerase regions .…”

“…Correspondingly, circulating HBV‐ and HCV‐specific CD8 + T cells highly expressed PD‐1 at the acute stage of infection . In acute HBV, envelope‐specific T cells expressed the highest levels of PD‐1 compared with virus‐specific T cells targeting core and polymerase regions . The degree of PD‐1 expression on HBV‐ and HCV‐specific T cells was positively correlated with markers of T‐cell activation, such as CD69, CD38, and HLA‐DR .…”

“…[17][18][19][20][21][22][23] In acute HBV, envelope-specific T cells expressed the highest levels of PD-1 compared with virus-specific T cells targeting core and polymerase regions. 23 The degree of PD-1 expression on HBV-and HCV-specific T cells was positively correlated with markers of T-cell activation, such as CD69, CD38, and HLA-DR. [18][19][20]24 At the acute phase of HCV infection in chimpanzees, the HCV-specific T cells were functional despite high PD-1 expression, and the highest IFN-γ responses were even seen when PD-1 expression levels peaked. 24 During acute HBV infection, the frequency of PD-1-expressing total CD8 + T cells as well as HBV-specific CD8 + T cells showed a positive correlation with serum ALT levels, suggesting functionally active PD-1-expressing T cells.…”

HBV antiviral immunity: not all CD8 T cells are born equal

“…The two manuscripts, Schuch et al 1 and Hoogeveen et al ,2 in Gut tackle this knowledge gap and undertake a direct and detailed ex vivo analysis of the phenotypic and functional features of CD8 T cells targeting epitopes located in different HBV proteins in patients with acute self-limited hepatitis B and in patients with eAg-negative chronic hepatitis B (CHB).…”