Macrophages direct location-dependent recall of B cell memory to vaccination [scRNA-seq and scVDJ-seq]

Vaccines generate long-lived plasma cells and memory B cells (Bmems) that may re-enter secondary germinal centers (GCs) to further mutate their B cell receptor upon boosting and re-exposure to antigen. We show that lymph nodes draining the primary vaccination site harbour a subset of Bmems that reside in the subcapsular niche, generate larger recall responses, and are more likely to re-enter GCs compared to circulating Bmems in non-draining lymph nodes. Depletion of CD169+ subcapsular sinus macrophages impairs Bmem proliferative expansion, secondary GC formation and secretion of affinity-matured antibodies upon boosting of the draining lymph node. This site-specific, niche-dependent control is associated with more rapid secretion of broadly neutralizing antibodies, GC participation and clonal expansion of SARS-CoV-2-specific B cells in healthy volunteers boosted with the BNT162b2 vaccine in the same versus opposite arm. These data reveal an unappreciated role for primed draining lymph node SSMs in Bmem cell fate determination.