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

Area of Science:

• Immunology
• Hepatology
• Virology

Background:

• Restoring B cell function is key for a chronic hepatitis B virus (CHB) functional cure, but targets are unclear.
• B cell defects contribute to the inability to clear HBV infection.
• Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA4) is a potential target in B cell restoration.

Purpose of the Study:

• To investigate the role of CTLA4 in B cell dysfunction in CHB patients.
• To explore CTLA4 as a therapeutic target for achieving a functional cure in CHB.
• To elucidate the mechanism by which CTLA4 affects B cell signaling.

Main Methods:

• Analysis of CTLA4 expression in peripheral and hepatic B cells from CHB patients.
• Single-cell RNA sequencing to assess signaling pathways in memory B cells.
• In vitro experiments depleting CTLA4 from B cells and in vivo studies using an HBV mouse model.

Main Results:

• CTLA4 was upregulated in HBsAg-specific B cells from CHB patients; peginterferon-α treatment reduced CTLA4 expression.
• CHB B cells showed diminished IL-6 JAK/STAT3 and IL-2/STAT5 signaling, correlating with impaired antibody secretion.
• CTLA4 depletion restored HBsAb secretion in vitro and improved anti-HBs humoral responses and viral clearance in an HBV mouse model.
• CTLA4 directly binds SHP-1, impairing Jak-STAT and B cell receptor signaling.

Conclusions:

• CTLA4 plays a significant role in B cell dysfunction in CHB.
• Targeting CTLA4 on B cells offers a promising strategy for a functional cure of CHB.
• Understanding CTLA4's mechanism provides a basis for novel therapeutic interventions.