Complement-regulated homeostatic proliferation controls memory B cell longevity and repertoire composition

Memory B cell (B_mem) survival is essential for guarding against reinfection, yet processes ensuring their longevity remain unclear. As decay-accelerating factor (DAF, CD55), a negative regulator of complement activation, is requisitely downregulated on germinal center B cells and is reexpressed on B_mem, we investigated the effects of deleting DAF on murine (B1-8^hi) B_mem in competitive settings. Kinetic analysis showed a progressive reduction in DAF^−/− B_mem numbers over 6 wk, without affecting B_mem production, pool size, or their ability to respond to rechallenge. Following transfer into unimmunized hosts, wild-type B_mem proliferated to maintain stable B_mem pool sizes, outcompeting DAF^−/− B_mem, reflecting homeostatic proliferation. Reduced proliferation and increased cell death in DAF^−/− B_mem associated with transcriptional differences in metabolism and migration pathways. Wild-type B_mem proliferation increased in C3^−/− hosts, and vaccination with a heterologous antigen, which induces local complement activation, locally inhibited bystander B1-8^hi B_mem proliferation. Thus, complement-dependent regulation of B_mem homeostatic proliferation influences B_mem longevity and repertoire composition in mice.