Affiliation:
1. IPGMER: Institute of Postgraduate Medical Education and Research
2. Institute of Postgraduate Medical Education and Research
Abstract
Abstract
Background and aims: Patients with chronic HBV infection (CHI) exhibit defective anti-viral immune-response whose underlying mechanisms remain unclear. Monocytes can regulate immunity via interaction with other immune-cells apart from differentiating into macrophages. Immune-checkpoint molecules (ICMs) expressed by different immune-cells, including monocytes negatively regulate immune-responses. We evaluated the expression of ICMs (Gal-9/PD-L1/CTLA-4) on monocytes in different phases of CHI, identified viral/host-factors causing their aberrant expression and investigated their impact during interaction of monocytes with T-/B-/NK-cells and macrophage differentiation. Effect of antiviral-therapy on ICMs was studied.
Methods: Collection of blood/liver-tissue samples/flow-cytometry/cell-sorting/cell-culture/immune-fluorescence were performed.
Results: Gal-9+/PD-L1+-monocytes were significantly increased in HBeAg-positive/HBeAg-negative chronic hepatitis B (CHB) patients than healthy controls (HC). In immune-tolerant (IT) subjects, Gal-9+-monocytes and in inactive carriers (IC), PD-L1+-monocytes were higher than HC while CTLA-4+-monocytes remained comparable among groups. High serum Hepatitis B surface antigen (HBsAg) concentration in IT/CHB and TNF-α in CHB triggered monocytic Gal-9-expression whereas high TNF-α/IL-4 in CHB and IL-1β in CHB/IC potentiated PD-L1 induction. Purified monocytes from CHB/IT having high Gal-9 expression led to expansion of CD4+CD25+FOXP3+-Tregs/CD19+CD27-CD21--atypical memory B-cells/CD19+IL-10+-Bregs and they preferentially differentiated into M2-macrophages. Anti-Gal-9-antibody reversed these phenomena. Parallelly, PD-L1+-monocytes in CHB/IC reduced IL-2/IFN-γ and IL-6-production by HBcAg-specific CD4+/CD8+T-cells and B-cells respectively, which were restored by anti-PD-L1-antibody. Gal-9+-/PD-L1+-monocytes caused decline in IFN-γ+-NK-cells but enhanced IL-10+-NK-cells and HBV-specific-T-cells. Increased intrahepatic CD14+Gal-9+/CD14+PD-L1+-monocytes was noted in CHB patients. One-year tenofovir-therapy failed to reduce monocytic Gal-9/PD-L1-expression and HBsAg/TNF-α/IL-4/IL-1β levels.
Conclusion: Monocyte-derived Gal-9/PD-L1 exert distinct inhibitory effects in different phases of CHI and their therapeutic targeting could boost anti-HBV immunity.
Publisher
Research Square Platform LLC