Sex-specific impact of B cell-derived IL-10 on tuberculosis resistance

David Hertz ¹ Sebastian Marwitz ¹ Lars Eggers ¹ Linda von Borstel ¹ Gishnu Harikumar Parvathy ¹ Jochen Behrends ¹ Danny Jonigk ² Rudolf Armin Manz ³ Torsten Goldmann ¹ Bianca E Schneider ^1*

• ¹ Research Center Borstel (LG), Borstel, Germany
• ² Institute for Pathology, University Hospital RWTH Aachen, Aachen, Nordrhein-Westfalen, Germany
• ³ University of Lübeck, Lübeck, Schleswig-Holstein, Germany

Due to the historical dogma, that host defense against intracellular pathogens is mediated by cellmediated immunity, B cells have been considered unimportant in providing protection against Mycobacterium tuberculosis (Mtb) and remained understudied for decades. However, emerging evidence suggests a more complex and multifaceted role for B cells in tuberculosis (TB) immunity. They accumulate at the side of infection in both animal models and human TB patients, suggesting a potential link to protective immunity. Still, the diverse roles of B cells in TB immunity continue to be unraveled. Apart from antibodies, B cells produce a wide range of cytokines, which can influence the local immune response. Here we addressed the relevance of interleukin 10 (IL-10) secreting B cells in long-term control of the Mtb Beijing strain HN878. Our research highlights the previously unknown role of B cell-derived IL-10 as a negative regulator of protective immunity in TB. For the first time, we demonstrate that mice lacking B cell-derived IL-10 show increased resistance to aerosol Mtb infection, as evidenced by a delayed onset of clinical symptoms and prolonged survival. Notably, this effect was significantly more pronounced in males compared to females, and was accompanied by male-specific immune alterations, indicating a previously unknown sex-specific regulatory role of B cell-derived IL-10 during Mtb infection.