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Inbred mice used for biomedical research display an underdeveloped immune system compared with adult humans, which is attributed in part to the artificial laboratory environment. Despite representing a central component of adaptive immunity, the impact of the laboratory environment on the B cell compartment has not been investigated in detail. Here, we performed an in-depth examination of B cells following rewilding, the controlled release of inbred laboratory mice into an outdoor enclosure. In rewilded mice, we observed B cells in circulation with increased signs of maturation, alongside heightened germinal center responses within secondary lymphoid organs. Rewilding also expanded B cells in the gut, which was accompanied by elevated systemic levels of immunoglobulin G (IgG) and IgM antibodies reactive to the microbiota. Our findings indicate that exposing laboratory mice to a more natural environment enhances B cell development to better reflect the immune system of free-living mammals. 

The paucity of blood granulocyte populations such as neutrophils in laboratory mice is a notable difference between this model organism and humans, but the cause of this species-specific difference is unclear. We previously demonstrated that laboratory mice released into a seminatural environment, referred to as rewilding, display an increase in blood granulocytes that is associated with expansion of fungi in the gut microbiota. Here, we find that tonic signals from fungal colonization induce sustained granulopoiesis through a mechanism distinct from emergency granulopoiesis, leading to a prolonged expansion of circulating neutrophils that promotes immunity. Fungal colonization after either rewilding or oral inoculation of laboratory mice withCandida albicansinduced persistent expansion of myeloid progenitors in the bone marrow. This increase in granulopoiesis conferred greater long-term protection from bloodstream infection by gram-positive bacteria than by the trained immune response evoked by transient exposure to the fungal cell wall component β-glucan. Consequently, introducing fungi into laboratory mice may restore aspects of leukocyte development and provide a better model for humans and free-living mammals that are constantly exposed to environmental fungi.