Compensatory relationships determine the impact of TGF-β on the humoral immune response to hepatitis B surface antigen.

Despite an effective vaccine against the hepatitis B virus (HBV), there are about 250 million people living with chronic HBV (CHB) worldwide and one million deaths annually. Most children and about 5% of adults exposed to HBV will fail to clear the virus, developing a lifelong infection. Hepatitis B surface antigen (HBsAg)-specific antibody (HBsAb) is protective in uninfected individuals and is considered a component of a functional cure. Immune factors that play important roles in regulating inflammation, such as TGF-β, IL-10, and regulatory T cells (Tregs), may also contribute to CHB pathogenesis. However, the early regulatory factors that promote HBsAg seroconversion are not well understood. To address this, we utilized adeno-associated virus (AAV)-mediated delivery of HBV (AAV-HBV) to mice. In this model, C57BL/6 mice fail to develop effective HBsAb responses, while BALB/c mice more efficiently seroconvert HBsAg. While inhibiting TGF-β, IL-10, or Tregs did not impact serum HBsAg levels in C57BL/6 mice, TGF-β depletion in BALB/c mice ablated the humoral response to HBsAg. Neutralizing IL-10, blocking CTLA-4, or depleting Tregs alone did not affect the HBsAb response in BALB/c mice. However, Treg depletion in the absence of TGF-β restored HBsAg clearance in an IL-10- and CTLA-4-independent manner. These findings highlight the immune balance regulated by TGF-β in the early adaptive response to an HBV antigen, as well as context-dependent compensatory interactions that may directly or indirectly impact antigen-specific humoral immunity.