Phase-specific polarization of peripheral helper T cells influences immunopathology and viral control in HBV infection.

[BACKGROUND] CD4 T cells orchestrate antiviral immunity but can also drive immunopathology in hepatitis B virus (HBV) infection. Peripheral helper T (Tph) cells are implicated in extra-lymphoid inflammation, yet their functional roles during HBV infection remain elusive.

[METHODS] We utilized single-cell RNA sequencing (scRNA-seq) to analyze intrahepatic and blood CD4 T cells from HBV-infected patients at various disease phases, including immune tolerant (IT), immune activation (IA), acute resolving (AR), and chronic resolved (CR). Multicolor immunohistochemistry (mIHC), single-cell multiplex secretome analysis, and functional experiments were conducted to validate the phenotypes of Tph and assess the impact of bile acid derivative tauroursodeoxycholic acid (TUDCA) on Tph cell functionality.

[RESULTS] We identified a Tph-like subset (PD-1CXCR5CXCL13) that is enriched in the liver and blood during both IA and AR phases of HBV infection. Despite their expansion in both phases, Tph cells exhibit striking functional dichotomy: AR-associated Tph cells displayed an effector-like antiviral program with increased cytotoxic signatures and secretion of IL-2, IL-7, IL-21, IFN-γ, and IL-10, whereas IA-associated Tph cells exhibited a pathogenic, pro-inflammatory phenotype dominated by TNF-α, GZMB, IL-4, and IL-9. Specifically, this polarization was putatively governed by the transcription factor balance between TBX21 and BHLHE40. Based on evidence that ER stress upregulates BHLHE40, we found that relief of ER stress by TUDCA repolarizes IA-phase Tph cells toward a protective, antiviral phenotype.

[CONCLUSIONS] These findings uncover the phase-specific plasticity of Tph cells and identify the ER stress-BHLHE40 axis as a potential therapeutic target to uncouple immunopathology from viral clearance in chronic hepatitis B.