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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-\u03b2, 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-\u03b2, IL-10, or Tregs did not impact serum HBsAg levels in C57BL\/6 mice, TGF-\u03b2 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-\u03b2 restored HBsAg clearance in an IL-10- and CTLA-4-independent manner. These findings highlight the immune balance regulated by TGF-\u03b2 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.<\/jats:p>","DOI":"10.1093\/jimmun\/vkag129","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T02:02:31Z","timestamp":1781748151000},"source":"Crossref","is-referenced-by-count":0,"title":["Compensatory relationships determine the impact of TGF-\u03b2 on the humoral immune response to hepatitis B surface antigen"],"prefix":"10.1093","volume":"215","author":[{"given":"Jesse L","family":"Cimino","sequence":"first","affiliation":[{"name":"Department of Immunology & Microbial Disease, Albany Medical College , Albany, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safiehkhatoon","family":"Moshkani","sequence":"additional","affiliation":[{"name":"Department of Immunology & Microbial Disease, Albany Medical College , Albany, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob T","family":"Bailey","sequence":"additional","affiliation":[{"name":"Department of Immunology & Microbial Disease, Albany Medical College , Albany, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Rexhouse","sequence":"additional","affiliation":[{"name":"Department of Immunology & Microbial Disease, Albany Medical College , Albany, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5614-153X","authenticated-orcid":false,"given":"Mitchell J","family":"Waldran","sequence":"additional","affiliation":[{"name":"Department of Immunology & Microbial Disease, Albany Medical College , Albany, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D","family":"Robek","sequence":"additional","affiliation":[{"name":"Department of Immunology & Microbial Disease, Albany Medical College , Albany, NY,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"2026090710435819000_vkag129-B1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nri3804","article-title":"Dynamics of B cells in germinal centres","volume":"15","author":"De Silva","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"2026090710435819000_vkag129-B2","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.3389\/fimmu.2018.02469","article-title":"Regulation of the germinal center response","volume":"9","author":"Stebegg","year":"2018","journal-title":"Front 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