Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT-cells in acute and chronic hepatitis B

Abstract

Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without Tcell based correlates of outcomes. To determine if &gama;δT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vd1+ and Vd2+&gama;δT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating &gama;δT-cells were comprised predominantly of CD3hiCD4-Vd2+&gama;δT-cells with frequencies that were 2-3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased TbethiEomesdim phenotype in Vd2+&gama;δT-cells whereas AHB was associated with increased TbethiEomesdim phenotype in Vd1+&gama;δT-cells, with significant correlations between Tbet/Eomes expression in &gama;δT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vd2+&gama;δT-cells were weaker in AHB but preserved in CHB, without significant differences for Vd1+&gama;δT-cells. Furthermore, early IFNγ/TNF responses in Vd2+ &gama;δT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vd2+&gama;δT-cells were and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating &gama;δT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes. weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating?dT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.