T cell-dependent B cell responses typically develop in germinal centers. Abs generated during such responses are isotype switched and have a high affinity to the Ag because of somatic hypermutation of Ab genes. B cell responses to purified polysaccharides are T cell independent and do not result in the formation of bona fide germinal centers, and the dominant Ab isotype produced during such responses is IgM with very few or no somatic mutations. Activation-induced cytidine deaminase (AID) is required for both somatic hypermutation and Ig isotype switching in humans and mice. To test the extent to which unmutated polysaccharide-specific IgM confers protective immunity, we immunized wildtype and AID mice with either heat-killed serovar Typhi ( Typhi) or purified Vi polysaccharide (ViPS). We found that wildtype and AID mice immunized with heat-killed Typhi generated similar anti-ViPS IgM responses. As expected, wildtype, but not AID mice generated ViPS-specific IgG. However, the differences in the Ab-dependent killing of Typhi mediated by the classical pathway of complement activation were not statistically significant. In ViPS-immunized wildtype and AID mice, the ViPS-specific IgM levels and Typhi bactericidal Ab titers at 7 but not at 28 d postimmunization were also comparable. To test the protective immunity conferred by these immunizations, mice were challenged with a chimeric Typhimurium strain expressing ViPS. Compared with their naive counterparts, immunized wildtype and AID mice exhibited significantly reduced bacterial burden regardless of the route of infection. These data indicate that an unmutated IgM response to ViPS contributes to protective immunity to Typhi.

B cell antigen receptor (BCR) diversity increases by several orders of magnitude due to the action of terminal deoxynucleotidyl transferase (TdT) during V(D)J recombination. Unlike adults, infants have limited BCR diversity, in part due to reduced expression of TdT. Since human infants and young mice respond poorly to polysaccharide vaccines, such as the pneumococcal polysaccharide vaccine Pneumovax23 and Vi polysaccharide (ViPS) of serovar Typhi, we tested the contribution of TdT-mediated BCR diversity in response to these vaccines. We found that TdT and TdT mice generated comparable antibody responses to Pneumovax23 and survived challenge. Moreover, passive immunization of B cell-deficient mice with serum from Pneumovax23-immunized TdT or TdT mice conferred protection. TdT and TdT mice generated comparable levels of anti-ViPS antibodies and antibody-dependent, complement-mediated bactericidal activity against Typhi To test the protective immunity conferred by ViPS immunization , TdT and TdT mice were challenged with a chimeric serovar Typhimurium strain expressing ViPS, since mice are nonpermissive hosts for Typhi infection. Compared to their unimmunized counterparts, immunized TdT and TdT mice challenged with ViPS-expressing Typhimurium exhibited a significant reduction in the bacterial burden and liver pathology. These data suggest that the impaired antibody response to the Pneumovax23 and ViPS vaccines in the young is not due to limited TdT-mediated BCR diversification.