Recall of B cell memory depends on relative locations of prime and boost immunization

Abstract

Immunization or microbial infection can establish long-term B cell memory not only systemically but also locally. Evidence has suggested that local B cell memory contributes to early local plasmacytic responses after secondary challenge. However, it is unclear whether locality of immunization plays any role in memory B cell participation in recall germinal centers (GCs), which is essential for updating their B cell antigen receptors (BCRs). Using single B cell culture and fate mapping, we have characterized BCR repertoires in recall GCs after boost immunizations at sites local or distal to the priming. Local boosts with homologous antigen recruit the progeny of primary GC B cells to recall GCs more efficiently than do distal boosts. Recall GCs elicited by local boosts contain significantly more B cells with elevated levels of immunoglobulin (Ig) mutation and higher avidity BCRs. This local preference is unaffected by blocking CD40:CD154 interaction to terminate active, GC responses. Local boosts with heterologous antigens elicit secondary GCs with B cell populations enriched for cross-reactivity to the prime and boost antigens; in contrast, cross-reactive GC B cells are rare after distal boosts. Our results suggest that local B cell memory is retained in the form of memory B cells, GC B cells, and GC phenotype B cells that are independent of organized GC structures and that these persistent “primed B cells” contribute to recall GC responses at local sites. Our findings indicate the importance of locality in humoral immunity and inform serial vaccination strategies for evolving viruses.

Abstract

The participation of memory B cells in recall germinal centers depends on whether the boost is local or distal to the priming site.

Local booster shots are superior

Germinal center (GC) responses to vaccination or infection generate memory B cells that contribute to long-term protective immunity. Whether location of immunization affects memory B cell recall into secondary GC responses remains to be determined. Kuraoka et al. used a prime boost immunization approach, whereby mice received a homologous antigen booster on the same (ipsilateral) or opposite (contralateral) leg. The magnitude and serum antibody responses were similar for ipsilateral and contralateral boosters; however, ipsilateral boosters elicited better quality GCs with higher avidity for antigen, higher immunoglobulin mutation frequencies, and increased recall of B cells from primary GCs. These results indicate that reactivation of local memory B cells generates superior secondary GC responses and suggest that location of booster immunization should be considered in vaccination strategies.