Tissue-directed maintenance of human B-cell memory after vaccination and infection 2260241

Abstract Introduction Vaccines differ in their efficacy and durability of protection. Clinical titer studies show that some, e.g. measles, confer lifelong immunity, while others wane within months or years. The memory B cells (MBCs) that sustain these responses reside mainly in lymphoid tissues, but it remains unclear whether these compartments maintain distinct subsets, how they contribute to vaccine immunity, and how they vary with age or antigen. Methods We profiled four ag-specific MBC populations, specific for childhood vaccines measles and tetanus and ubiquitous viruses SARS-CoV-2 and H1N1 influenza, across paired blood, spleen, lymph nodes, and bone marrow, by flow cytometry and paired single-cell RNA and B-cell receptor (BCR) sequencing. Results MBC isotype, subset, and phenotype differed markedly between tissue sites, specificity, and age. Lymph nodes were reservoirs for classical IgG+ memory with high expression of the residency marker CD69. In other sites, whereas measles retained a classical phenotype, tetanus MBCs were enriched for non-switched memory. Notably, SARS-CoV-2 and influenza responses were highly switched but, with age, uniquely accumulated hyporesponsive CD27- CD21- atypical memory in the blood, bone marrow, and spleen. RNA sequencing resolved three core MBC subsets enriched in distinct tissues: tissue-adapted classical MBCs in lymph nodes, marginal zone—like MBCs in spleen, and atypical MBCs in bone marrow. All three subsets were represented within ag-specific populations, but their relative proportions were shaped by both tissue and antigen. Clonal and phylogenetic analyses revealed that expanded ag-specific clones, including cells with identical BCRs, spanned multiple subsets, indicating that MBC identity is flexible but primarily shaped by local context rather than lineage. Conclusion This work uncovers functionally distinct tissue reservoirs of vaccine and infection-induced memory and the host and antigen factors that shape them, highlighting new opportunities for vaccine design. Funding Source NIH U19 AI128949, DARPA Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)