Alugupalli, Kishore R.

Although evidence of the protective immunity conferred by B‐1b cells (CD19+B220+IgMhiMac1+CD5−) has been established, the mechanisms governing the maintenance and activation of B‐1b cells following pathogen encounter remain unclear. B cell–activating factor (BAFF) and a proliferation‐inducing ligand (APRIL) mediate their function in mature B cells through the BAFF receptor (BAFFR) and transmembrane activator and CAML interactor (TACI). BAFFR‐deficient mice have lower numbers of B‐1b cells, and this reduction is directly proportional to BAFFR levels. The generation of B‐1b cells is also dependent on the strength of B cell receptor (BCR) signaling. Mice with impaired BCR signaling, such as X‐linked immunodeficient (xid) mice, have B‐1b cell deficiency, indicating that both BCR‐ and BAFFR‐mediated signaling are critical for B‐1b cell homeostasis. Borrelia hermsii induces expansion and persistence of B‐1b cells in xid mice, and these B‐1b cells provide a heightened protective response. Toll‐like receptor (TLR)–mediated stimulation of xid B cells results in a significant increase in TACI expression and restoration of TACI‐mediated functions. The activation of TLR signaling by B. hermsii and BCR/TLR costimulation–mediated upregulation of BAFFR and TACI on B‐1b cells suggests that B‐1b cell maintenance and function following bacterial exposure may depend on BAFFR‐ and TACI‐mediated signaling. In fact, the loss of both BAFFR and TACI results in a greater impairment in anti‐B. hermsii responses compared to deficiency of BAFFR or TACI alone.

Abstract Immune response to T cell independent type 2 (TI-2) Ags, such as bacterial polysaccharides, is severely impaired in X-linked immunodeficient (XID) mice. In this study, we investigated the involvement of a proliferation-inducing ligand (APRIL) or BAFF and their receptors in the unresponsiveness of XID mouse to TI-2 Ags. We discovered that whereas serum BAFF levels were increased, the expression of the APRIL and BAFF receptor transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) was severely reduced in XID B cells. Moreover, B cells from XID mouse were unable to secrete Igs in response to APRIL or BAFF. In correlation with reduced TACI expression and impaired TACI function, APRIL or BAFF did not activate the classical NF-κB pathway in XID cells. Also correlating with the unaltered expression of BAFF receptor, BAFF stimulation induced the activation of the alternative NF-κB pathway in XID cells. Moreover, activation of MAPK pathway was ablated in APRIL-stimulated XID cells. Prestimulation of XID B cells with the TLR9 agonist, CpG led to a significant increase in TACI expression and restored TACI-mediated functions. CpG prestimulation also restored TACI-mediated signaling in APRIL- or BAFF-stimulated XID B cells. Finally, immunization of XID mouse with the prototype TI-2 Ag NP-Ficoll induced IgG and IgM Abs when CpG was given with NP-Ficoll. Collectively, these results suggest that reduced TACI expression is responsible for the unresponsiveness of XID mouse to TI-2 Ags and BCR activation controls TACI expression.

ABSTRACT 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.