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J Hepatol. 2014 Dec;61(6):1212-9. doi: 10.1016/j.jhep.2014.07.005. Epub 2014 Jul 10.

Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation.

Author information

1
Department of Medicine II, University Hospital of Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Germany; Faculty of Biology, University of Freiburg, Germany.
2
Department of Medicine II, University Hospital of Freiburg, Germany. Electronic address: Robert.Thimme@uniklinik-freiburg.de.

Abstract

BACKGROUND & AIMS:

The upregulation of several inhibitory signalling pathways by exhausted HBV-specific CD8+ T cells in chronic infection is thought to contribute to viral persistence. Blockade of inhibitory receptors to reinvigorate exhausted T cell function is a promising novel therapeutic approach. However, little information is available regarding the relative contribution of individual inhibitory pathways to HBV-specific CD8+ T cell failure and the impact of inhibitory receptor blockade on restoration of T cell function in chronic HBV.

METHODS:

98 HLA-A2+ chronically infected patients were analysed ex vivo for HBV-specific CD8+ T cell responses, the expression of multiple inhibitory receptors and T cell differentiation markers. The effects of inhibitory receptor blockade targeting PD-1, 2B4, Tim-3, CTLA-4, and BTLA were assessed in vitro.

RESULTS:

In our cohort, ex vivo HBV-specific CD8+ T cell responses were identified preferentially in HBeAg patients with low ALT and low viral load (inactive carriers). We observed a clear hierarchy of inhibitory receptor expression dominated by PD-1. The response to inhibitory receptor blockade was heterogeneous. Compared to the blockade of other inhibitory receptors, blockade of the PD-1 pathway resulted in the strongest increase in function. Of note, a positive effect of PD-1 blockade was linked to intermediate T cell differentiation.

CONCLUSIONS:

Despite the expression of multiple inhibitory receptors by HBV-specific CD8+ T cells, expression and response to blockade was dominated by PD-1. However, PD-1 expression did not predict response to blockade. Rather, response to blockade was associated with intermediate T cell differentiation. These findings have important implications for our understanding of inhibitory receptor blockade as a novel therapeutic strategy.

KEYWORDS:

HBV; Inactive carrier; Inhibitory receptors; PD-1; T cell differentiation; T cell exhaustion; Virus-specific CD8+ T cells

PMID:
25016223
DOI:
10.1016/j.jhep.2014.07.005
[Indexed for MEDLINE]

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