The immune landscape and mechanism of hepatitis B virus surface antigen clearance [CITEseq]

Hepatitis B virus (HBV) surface antigen (HBsAg) clearance constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic hepatitis B. Here, we reveal the immunological landscape and mechanism of HBsAg clearance in mice. After acquiring nonopsonized HBsAg, B cells prime CD4+ T cell responses by CCR5- and EBI2-guided interaction with CD4+ T cells at follicular and interfollicular regions, respectively. Monocyte-derived macrophages transport complement-opsonized HBsAg to follicular dendritic cells (FDCs) to maintain germinal center reaction. Batf3+ XCR1+ conventional type 1 DCs (cDC1s) acquire and present HBsAg by MHC-I cross-dressing to drive CD8+ T cell responses in liver. We map the antigen-presenting cell (APC)-T cell crosstalk landscape and identify key costimulatory signals. The immune responses in patients with acute HBV infection are revealed by a single-cell transcriptome atlas. These findings revolutionize our understanding of anti-HBV immune responses and would lead to immunotherapeutic strategies for HBsAg clearance. Overall design: To study the heterogeneity of CD4+ T cell differentiation fate in response to HBsAg, we adoptively transferred OT-II T cells into congenic WT hosts and profiled FACS-sorted OT-II T cells form the spleen, dLN and liver by scRNA-seq at day 7 after injection with pHBV1.3/OVA323-339. To identify the APC subsets and underlying mechanisms of cellular interaction responsible for HBsAg-specific CD8+ T cell responses in liver, we performed scRNA-seq on sorted CD11chighMHCII+ DCs, hepatocytes and OT-I T cells from liver at days 0 and 2.5 after the hydrodynamic injection of pHBV1.3/OVA257-264.