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.

B cell intrinsic and extrinsic factors impacting memory recall responses to SRBC challenge

“…A still lower contribution of MBCs to recall GCs was reported in the setting of a boost in the contra-lateral footpad, but values similar to ours were mentioned in this study for an intraperitoneal immunization ( 20 ). This is in line with a recent paper which shows the preferential participation of MBCs to recall GCs in local boost condition ( 32 ). In the case of an SRBCs challenge that generates robust secondary GCs comprising several millions of cells, the contribution of MBCs, even minor, still represents a considerable cell fraction that will undergo new rounds of maturation.…”

Time is of the essence for vaccine success

“…A second is that with the detection of shared clones with high mutational load in lymph nodes at different sites and in the blood, the data of Lee et al 2 are consistent with MBCs re-entering ongoing GCs for further affinity maturation and selection. In contrast to the potentially insignificant participation of MBCs reported during secondary GC responses 11 , re-recruitment here, in particular within the same anatomical site 12 , may commonly occur. That is, the observed rarity of MBCs with low mutational load could either be due to their gradual consumption through repeated re-entry or reflect a ‘dilution’ through continued MBC output.…”

Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells

“…Serum antibody titers were higher after ipsilateral versus contralateral boosting. A recent report indicated that affinity maturation was also enhanced by same-site boosting, suggesting that ipsilateral boosting may offer advantages for humoral immunity ( 61 ). Opposite-site boosting readily affected T cell responses.…”