Efficient B cell responses to Borrelia hermsii infection depend on BAFF and BAFFR but not TACI.

T cell-independent antibody responses develop rapidly, within 3 to 4 days, and are critical for preventing blood-borne pathogens from evolving into life-threatening infections. The interaction of BAFF, also known as BLyS, with its receptors BAFFR and TACI on B cells is critical for B cell homeostasis and function. Using a synthetic polysaccharide antigen, it has previously been shown that TACI is critical for T cell-independent antibody responses. To examine the role of BAFFR and TACI in T cell-independent antibody responses to an active infection, we utilized the Borrelia hermsii infection system. In this infection system, T cell-independent responses mediated by the B1b cell subset are critical for controlling bacteremia. We found that B1b cells express BAFFR and TACI and that the surface expression of both receptors is upregulated on B1b cells following exposure to whole B. hermsii cells. Surprisingly, we found that TACI(-/-) mice are not impaired either in specific antibody responses to B. hermsii or in controlling B. hermsii bacteremia. In contrast, TACI-deficient mice immunized with heat-killed type 3 serotype pneumococcus cells are impaired in generating pneumococcal polysaccharide-specific responses and succumb to challenge with live type 3 serotype pneumococcus, indicating that TACI is required for T cell-independent antibody responses to bacterial-associated polysaccharides. Although we have found that TACI is dispensable for controlling B. hermsii infection, mice deficient in BAFFR or BAFF exhibit impairment in B. hermsii-specific IgM responses and clearance of bacteremia. Collectively, these data indicate a disparity in the roles for TACI and BAFFR in primary T cell-independent antibody responses to bacterial pathogens

Interleukin-7-dependent B lymphocytes are required for the anti-pneumococcal polysaccharide response and protective immunity to Streptococcus pneumoniae

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