CTLA4 modulates B cell receptor signals to inhibit HBsAb secretion in chronic hepatitis B patients

Restoring B cell defects is crucial to achieve the functional cure of chronic hepatitis B virus (CHB) infection, yet the specific targets remain largely unexplored. Our study identified that CTLA4 was highly upregulated in both peripheral and hepatic HBsAg-specific B cells from CHB patients, while effective peginterferon-α treatment could reduce the frequency of CTLA4⁺HBsAg⁺ B cells. Single-cell RNA-seq analysis revealed that the diminished IL-6 JAK/STAT3 and IL-2/STAT5 signaling pathways in memory B cells from CHB patients,which might contribute to the incapability of HBsAb antibody secretion. CTLA4⁺ B cells, especially from CHB patients, consistently showed defective responses in B cell receptor signaling and inflammatory responses compared to CTLA4⁻ B cells. Notably, CTLA4 depletion partially restored the secretion of HBsAb in vitro from peripheral B cells from CHB patients, but also could restore anti-HBs humoral responses and potentiate viral clearance in HBV mouse model. Mechanistic analysis revealed that CTLA4 is directly bound to SHP-1, resulting in the impaired Jak-STAT and B cell receptor signaling pathway. Collectively, our data highlights an unappreciated role of CTLA4 on B cell responses. Targeting CTLA4 on B cells holds promise to achieve the functional cure of CHB patients.