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Unlike human adults or adult mice, young children or young mice respond poorly to pneumococcal polysaccharides (PPS). In mice, B1b lymphocytes are the major responders to a variety of bacterial polysaccharides including PPS. Despite having B1b cells, young mice are severely impaired in responding to PPS, suggesting that B cells in the young are distinct from those in adults. Since B lymphopoeisis early in life is largely Interleukin-7 (IL-7)-independent, while in adults it is IL-7-dependent, we hypothesize that B cells developed in the presence of IL-7 are required for generating anti-PPS antibody responses. In support of this, we found that despite having B1b cells, young wildtype and adult mice deficient either in IL-7 or IL-7Rα are severely impaired in responding to Pneumovax®23 vaccine, and do not survive pneumococcal challenge. Furthermore, we found that transgenic expression of IL-7 promotes the anti-PPS response in young and confers protective immunity to young mice. To translate these findings to human infants we have utilized neonatal NOD/SCID/gcnull mice engrafted with human umbilical cord blood CD34+ hematopoietic stem cells to create a "Human Immune System" mouse (HISmouse) model. We have found that these HISmice generate several B cell subsets including B1 (CD19+CD20+CD27+CD43+CD70-CD69-) and the majority of them exhibit an immature phenotype. Moreover, just as young children, HISmice responded poorly to PPS. IL-7 is produced mainly by non-hematopoietic stromal cells, and unlike the human IL-7, the murine IL-7 is poor stimulator of human B lymphocyte development. Although our data indicate that IL-7-dependent B cells are crucial for generating anti-polysaccharide response, we also found that enforced expression of a polysaccharide (a1,3, dextran)-specific B cell antigen receptor heavy chain (VH J558) in mice can overcome the lack of anti-polysaccharide antibody responses in young mice even in the absence of an IL-7-dependent B lymphopoiesis.