Antibody responses to classical T cell-independent (TI) antigens such as bacterial capsular polysaccharides are highly protective, and play a critical role in controlling a number of clinically important infections. For reasons that remain poorly understood young children cannot mount antibody responses to TI antigens and as a consequence are much more prone to suffer from life-threatening infections, particularly from encapsulated bacterial pathogens. As with young children, young mice respond poorly to polysaccharide antigens, while human adults as well as adult mice can mount a very efficient response to polysaccharide antigens. B1b lymphocytes are a subset of mature B cells that increases in number in response to a variety of TI antigens including type 3 polysaccharide of Streptococcus pneumoniae (PPS3), ?1,3 dextran of Enterobacter cloacae, Vi polysaccharide of Salmonella typhi and Factor H binding protein A, a surface antigen of Borrelia hermsii. Furthermore, these cells generate rapid primary antibody as well as long-lasting memory B cell responses. Despite having B1b cells, young mice are impaired in responding to polysaccharide antigens, suggesting that B cells in the young are distinct from those in adults. Since B lymphopoeisis early in life is largely 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-polysaccharide antibody responses. In support of this, we found that despite having B1b cells, young wildtype, adult IL-7-/- or adult IL-7R?-/- mice are severely impaired in responding to classical TI antigens such as 4-hydroxy-3-nitrophenyl-acetyl-Ficoll (NP-Ficoll), bacterial dextran and PPS vaccine, and do not survive S. pneumoniae challenge after PPS immunization. Furthermore, we found that transgenic expression of IL-7 promotes the anti-PPS response in young and confers protective immunity to S. pneumoniae. These data support the hypothesis that IL-7-dependent B cells play a crucial role in generating TI humoral immunity. To translate these findings to human infants we have utilized neonatal NOD/SCID/?cnull 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 subsets of B cells including B1 cells and the majority of them exhibit an immature B cell phenotype. Moreover, just as young children, HISmice responded poorly to PPS and sub-optimally to B. hermsii. Since IL-7 is produced mainly by non-hematopoietic stromal cells, and murine IL-7 is poor stimulator of human lymphocyte development, this impairment could be due to the lack of human IL-7-driven B cells in HISmice. In support of this we found that supplementation of HISmice with human IL-7 dramatically increases humoral responses to B. hermsii.
The aims outlined in this proposal seek to: 1) determine whether IL-7 increases the number of polysaccharide- specific B1b cells;and 2) determine whether the B1b cells generated in the presence or absence of IL-7 are qualitatively different.
Infectious diseases are the leading cause of infant mortality and morbidity worldwide, and vaccination is the most effective way to control them. Polysaccharide vaccines do not generate immune responses in the young, and as a consequence are much more prone to suffer from life-threatening infections, particularly from capsulated bacteria. Understanding the molecular basis for protective responses conferred by interleukin-7 dependent B1b cells will provide novel approaches to generate effective polysaccharide vaccines for infants and young children.