The control of B-1 cell dynamics and natural antibody production by the C5a/C5aR axes
B-1 lymphocytes are innate-like B cells secreting natural IgM (nIgM) antibodies without previous antigen exposure. These antibodies mediate first-line defense against bacteria and viruses before adaptive immune responses establish. B-1 cells are predominantly located inside body cavities and in lower numbers in spleen and bone marrow. B-1 cell homing to the peritoneal cavity is mediated by the chemokine CXCL13, but the underlying mechanisms controlling CXCL13 production remain elusive. Germ-free mice have increased numbers of B-1 cells in their peritoneal cavity as compared with SPF-housed mice suggesting that microbial signatures drive B-1 cell trafficking out of the peritoneum into the spleen where they differentiate into plasma cells and produced nIgM antibodies. Microbial patterns are strong activators of complement. In this project we found that C5a receptor 1 (C5aR1) and C5aR2-deficient mice showed significantly reduced peritoneal B-1 cell numbers which was associated with increased B-1 cell numbers in the spleen (Bröker et al. Front Immunol 2018). Accordingly, C5aR1-deficient mice had elevated serum levels of nIgM against phosphorylcholine and different polysaccharides of Streptococcus pneumoniae. In this project we are working on the of C5a/C5aR1/C5aR2 axes in the regulation of B-1 biology focusing on B-1 cell homeostasis in the peritoneal cavity, nIgM production and inflammation-driven egress from the peritoneum into the spleen.
Figure 5: Interaction between B1 cells and macrophages in the peritoneal cavity. 1) activation of B1 cell via Toll-like receptors (TLR) cause 2) IL-10 release, which synergizes with TLR ligands to activate macrophages. Such activated macrophages express intracellularly C5 and proteases capable to cleave 3) C5 into C5a and C5b in a non-canonical way. Subsequent C5a binding to the C5aR1 enhances the IL-10/TLR-induced 4) CXCL13 production which is essential for B1 cell homeostasis.