Hierarchy of inhibitory receptor expression by Hepatitis B Virus (HBV)-specific CD8+ T cells in chronic HBV infection

Abstract

Virus-specific CD8+ T cells are thought to play a crucial role in the immunobiology of HBV infection. In chronic HBV infection, up-regulation of several inhibitory signaling pathways by HBV-specific CD8+ T cells is thought to contribute to viral persistence. However, the relative contribution of the individual inhibitory pathways has not been addressed so far. In this study, we determined the coexpression of multiple inhibitory receptors (PD–1, 2B4, CD160, KLRG1 and Tim–3) ex vivo by HBV-specific CD8+ T cells from 17 patients (16 HBeAg neg., 1 HBeAg pos.) with significant HBV-specific T cell frequencies and compared it to CD8+ T cells specific for other viruses (FLU, CMV, HCV). The differentiation stage of virus-specific CD8+ T cells was analyzed by CCR7, CD27 and CD45RA expression. We found that the coexpression of inhibitory receptors was associated with intermediate T cell differentiation stages. Further, HBV-specific CD8+ T cells expressed higher amounts of PD–1 and 2B4 compared to CD160, KLRG1 and Tim–3. PD–1+2B4+ HBV-specific CD8+ T cells were enriched intrahepatically compared to the peripheral blood. The expression pattern of inhibitory receptors clearly differed between HBV-specific (high PD–1 and 2B4 expression) and Influenza- (high Tim–3 expression) or CMV-specific CD8+ T cells (high 2B4 and KLRG1 expression) but showed a similarly high expression of PD–1 and 2B4 with HCV-specific CD8+ T cells, suggesting a common hierarchy of inhibitory receptor expression between CD8+ T cells specific for hepatitis B and C viruses. These results suggest a hierarchy of inhibitory receptor expression by HBV-specific CD8+ T cells dominated by PD–1 and 2B4. They also suggest a rationale for the therapeutic targeting of these inhibitory receptor pathways in chronic HBV infection.