Dynamic regulation of B cell complement signaling is integral to germinal center responses.

Abstract

B cell maturation within germinal centers (GCs) generates diversified B cell pools and high-affinity B cell antigen receptors (BCRs) for pathogen clearance. Increased receptor affinity is achieved by iterative cycles of T cell-dependent, affinity-based B cell positive selection and clonal expansion by incompletely understood mechanisms. Here, we found that as part of a physiologic program, GC B cells repressed expression of decay-accelerating factor (DAF/CD55) and other complement C3-convertase regulators via Bcl-6, but increased C5b-9 inhibitor (CD59) expression. These changes permitted C3 cleavage on GC B cell surfaces, without membrane attack complex formation, and activated C3a-receptor and C5a-receptor signals required for positive selection. Genetic disruption of this pathway in antigen-activated B cells, by conditional transgenic DAF overexpression or deletion of C3a and C5a receptors, limited mTOR activity in response to BCR-CD40 signaling, causing premature GC collapse and impaired affinity maturation. These results reveal that coordinated shifts in complement regulation within the GC provide crucial signals underlying GC B cell positive selection.