Lymphotoxin Signaling is Essential in the Generation of Protective Responses to Mucosal Vaccines

Although oral vaccination offers many practical advantages, the generation of long-lived protective immunity following inoculation is poorly understood. Using oral vaccination of live, attenuated Salmonella to establish persistent colonization of mice, we demonstrate that the lymphotoxin pathway is essential for the generation of protective immunity to mucosal infection. It was previously shown that LTβR deficient mice have normal colonization of Salmonella in the gut. However, we find that mice deficient in this pathway fail to generate protective immunity following persistent oral vaccination, and succumb to a secondary challenge with virulent Salmonella. To determine if LTβR^-/- animals fail to develop antibody responses, we measured titers of anti-Salmonella IgM and IgG. Although these mice develop normal levels of IgM, they fail to produce anti-Salmonella IgG, implying a role for lymphotoxin in class switching. Animals that lack LTβR have an absence of Peyer’s patches and lymph nodes. Surprisingly, we find that lymphotoxin plays an essential role in antibody production independently of its role in lymphoid tissue development, as short-term treatment of WT mice with blocking LTβR-Ig is sufficient to prevent the formation of anti-Salmonella antibody responses. Using genetic approaches we further dissect the contribution of lymphotoxin in generating protective responses to mucosal vaccination.