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How some bacteria evade the immune system to cause persistent infection is unclear. Oral vaccination against bacterial pathogens could limit lethal infection but the immune pathways that generate protective immunity are poorly understood. Using streptomycin pretreatment and oral vaccination with live, attenuated Salmonella to establish persistent colonization of mice, we demonstrate that the lymphotoxin pathway is essential for the generation of protective immunity to Salmonella infection. Lymphotoxin beta receptor (LTβR) deficient mice have normal initial colonization of attenuated Salmonella in the gut but fail to achieve clearance of Salmonella from the feces, and die following challenge with virulent Salmonella. Using a gnotobiotic approach we show that even with the same input microbiota, LTβR signaling drives microbiota-mediated clearance of Salmonella. The role of LTβR in Salmonella protective responses is not limited to mucosal infection, as LTβR deficient mice vaccinated and challenged intraperitoneally also succumb to challenge. Antibody responses to Salmonella occurring in the spleen are extrafollicular and contribute to protection. To examine whether antibody responses were deficient in LTβR-/- mice, we measured serum concentrations of anti-Salmonella IgM and IgG. Although LTβR-/- mice have levels of serum anti-Salmonella IgM similar to LTβR sufficient controls, they fail to produce anti-Salmonella IgG, implying a role for lymphotoxin in class switching. Surprisingly, we find that lymphotoxin (LT) plays an essential role in Salmonella immunity independent of its role in secondary lymphoid tissue development; treatment of WT mice with LTβR-Ig is sufficient to reduce the formation of anti-Salmonella antibody responses and increase persistence of Salmonella in the gut. Using mice conditionally deficient in LT beta (LTβ), we find that B cell (CD19Cre) derived lymphotoxin is essential for anti-Salmonella IgG responses. Finally, we show that multiple cellular sources of lymphotoxin, especially B cells and likely ILC3 (RorcCre), but not T cells (CD4Cre), contribute to protection against challenge with virulent Salmonella. Together these data demonstrate the essential role of the LT/LTβR signaling pathway in the generation of immunity to Salmonella infection.


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