Macrophages direct location-dependent recall of B cell memory to vaccination

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 in mouse models that lymph nodes draining the site of primary vaccination harbor a subset of Bmems that reside in the subcapsular niche, generate larger recall responses, and are more likely to re-enter GCs compared with circulating Bmems in non-draining lymph nodes. This location-dependent recall of Bmems into the GC in the draining lymph node was dependent on CD169⁺ subcapsular sinus macrophages (SSMs) in the subcapsular niche. In human participants, boosting of the BNT162b2 vaccine in the same arm generated more rapid secretion of broadly neutralizing antibodies, GC participation, and clonal expansion of SARS-CoV-2-specific B cells than boosting of the opposite arm. These data reveal an unappreciated role for primed draining lymph node SSMs in Bmem cell fate determination.