B cell activating factor (BAFF) from neutrophils and dendritic cells is required for protective B cell responses against Salmonella typhimurium infection

Abstract

Mice lacking B cells are more susceptible to S. typhimurium infection. How B cells contribute to protective immunity against Salmonella and what signals drive their activation are still unclear. Neutrophils (Nphs), monocytes (MOs), and dendritic cells (DCs) are involved in early immune responses to control the initial replication of S. typhimurium. These cells can produce B cell activating factor (BAFF) required for mature B cell survival and may help regulate B cell responses during Salmonella infection. Using BAFF reporter mice (BAFF-RFP+/-), we discovered that an i.p. infection with a virulent strain of S. typhimurium increased BAFF expression in splenic conventional DCs (cDC) and inflammatory Ly6Chi MOs/DCs four days post-infection. S. typhimurium infection induced the release of BAFF from Nphs, a decrease of BAFF-RFP expression and expansion of BAFF-RFP+ Nphs in the spleen and peritoneal cavity. After S. typhimurium infection, serum BAFF levels and immature and mature B cell subsets and plasma cells increased substantially. Conditional knockout (cKO) mice lacking BAFF in either Nphs or cDCs compared to control Bafffl/fl mice had reduced up-regulation of systemic BAFF levels and reduced expansion of mature and germinal center B cell subsets after infection. Importantly, the cKO mice lacking BAFF from either Nphs or cDCs had impaired induction of Salmonella-specific IgM Abs, and were more susceptible to S. typhimurium infection. Thus, Nphs and cDCs are major cellular sources of BAFF driving B cell responses, required for mounting optimal protective immunity against lethal Salmonella infection.

B cell class switching in intestinal immunity in health and disease

“…TI responses by marginal zone B cells in the spleen can also be induced in both a contact‐dependent and contact‐independent manner by a broad range of innate cells, including neutrophils, 17 dendritic cells (DCs) 18 and mast cells. 19 These innate ‘B helper cells’ have been shown to be important (in mice) for protection from a range of pathogens including S typhimurium 20 and West Nile Virus. 21 The reliance on innate cells in these responses has led to the proposal that they may constitute a “TI‐3” response distinct from TI type 1 and TI type 2 responses.…”

B cell-activating factor (BAFF) from dendritic cells, monocytes and neutrophils is required for B cell maturation and autoantibody production in SLE-like autoimmune disease

“…In contrast to the TLR7 Tg mice, splenic Nphs from BAFF-RFP Sle1 mice had lower BAFF expression per cell than Nphs from BAFF-RFP controls (Figures 3A, B), possibly due to Nph activation. Indeed, we and others have shown that upon activation, Nphs not only release BAFF from the intracellular stores but also down-regulate BAFF expression (11). cDC-and B cell-BAFF expression per cell did not change in the spleens of Sle1 autoimmune mice (Figure 3B).…”

“…Heterozygous BAFF-RFP +/-(BAFF-RFP) mice express lower BAFF levels, as one Baff allele expresses the RFP protein as a measurement of BAFF expression and the other allele expresses wild-type (WT) Baff (10, 11). However, BAFF-RFP still retain a reduced population of mature B cells, and thus can be used for functional studies of B cells and Ab responses (10,11). We first assessed how either the Tlr7.1 Tg or the Sle1 background affected serum BAFF levels.…”

“…In order to explore the effects of depletion of BAFF in specific immune cell types, we used a pristane-induced mouse model of lupus (10,11). As with Tlr7Tg mice, the SLE-like autoimmune phenotype of PIL mice is dependent on IFN-I production and expansion of inflammatory myeloid cells (39).…”

“…Baff -/and Baffr -/mice develop few or no mature B cells due to a block in B cell development from the newly formed transitional 1 (T1) to the T2 B cell stage onwards (5)(6)(7). We and others have shown that BAFF plays a key protective role against infectious diseases, including West Nile virus, HIV and Salmonella typhimurium (8)(9)(10)(11)(12).…”