The core cellular network modulates immune phenotype switching in hepatitis B

Hepatitis B virus (HBV) is a leading cause of liver-related diseases and mortality. However, immune mechanisms governing the phases of HBV infection remain elusive. Understanding molecular components in hepatitis immunosuppression and progression is essential for developing immunotherapies for functional cure of chronic HBV infection. Our integrative analysis of intrahepatic tissue and peripheral PBMC samples from patients with acute and chronic HBV infection using single-cell RNA sequencing (scRNA-seq) and TCR/BCR sequencing (scTCR/BCR-seq) revealed three distinct lineages of PBMC-derived intrahepatic T lymphocytes (hpCTLs): exhausted GZMK+PDCD1+, short-lived effector KLRG1+, and inactivated GZMB+PRF1+ hpCTLs. Key factors such as FasL/Fas-mediated cytotoxicity, CD28 co-stimulation, and exhaustion status were identified as determinants of hpCTL functionality. Liver-resident DC-SIGN+ macrophages were found to act as antigen-presenting cells that cross-prime hpCTLs in response to IL-2 or as suppressive macrophages by inhibiting T cell immunity through IL-10 and PD-L1 production and Treg recruitment. The intrahepatic core cellular network, including DC-SIGN+ macrophages, CSF1+ST2+ mast cells, AREG+ liver-resident NK cells, CD14+ hepatocytes, and CXCL13+ TFH, was observed to modulate immune tolerance, activation, and suppression in HBV infection. This study inferred the core cellular network involved in immune phenotype switching across different hepatitis B phases and suggested potential immunomodulatory strategies for treating chronic HBV infection. We performed single-cell RNA sequencing (scRNA-seq) on liver biopsy samples from patients with HBV infection, which included 3 cases in the acute hepatitis (AHB) phase, 5 cases in the immune tolerance (IA) phase, 5 cases in the immune clearance (IC) phase, 5 cases in the immune transition (IT) phase and 3 healthy control cases. Additionally, paired peripheral PBMC samples were analyzed, comprising 3 cases in the AHB phase, 3 cases in the IA phase, 5 cases in the IC phase, and 4 cases in the IT phase. *************************************************************** Raw files for human/patient samples are being made available in GSA (https://ngdc.cncb.ac.cn/gsa/) for controlled access to the personally identifiable sequence data (BioProject PRJCA031773, with the assigned accession number HRA009171). ***************************************************************