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.
Polysaccharide vaccines such as the Vi polysaccharide (ViPS) of serovar Typhi induce efficient Ab responses in adults but not in young children. The reasons for this difference are not understood. IL-7 dependency in B cell development increases progressively with age. IL-7Rα-mediated signals are required for the expression of many V gene segments that are distal to D-J in the IgH locus and for the complete diversification of the BCR repertoire. Therefore, we hypothesized that B cells generated in the absence of IL-7 do not recognize a wide range of Ags because of a restricted BCR repertoire. Compared with adult wildtype mice, young wildtype mice and IL-7-deficient adult mice generated a significantly reduced Ab response to ViPS. Additionally, ViPS-binding B cells in adult wildtype mice predominantly used distal V gene segments. Transgenic expression of either IL-7 or a BCR encoded by a distal V gene segment permitted young mice to respond efficiently to bacterial polysaccharides. These results indicate that restricted V gene usage early in life results in a paucity of Ag-specific B cell precursors, thus limiting antipolysaccharide responses.
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