Abstract
Abstract Thymic resident B cells were reported for the first time more than 40 years ago. Yet, their phenotype and significance remain unclear. In this study, we investigated the heterogeneity of thymic B cells in neonates as an indication of their possible function. Using thymuses from 21 neonates, we observed two consistent subsets, CD19+CD21+CD35+ and CD19+CD21−CD35−, accounting for virtually all thymic B cells. ELISPOT assays revealed the presence of IgG, IgA, IgM and even IgE antibody-secreting cells within the CD21−CD35− subset but not the CD21+CD35+ subset. To characterize the heterogeneity of CD21−CD35− subset, we used a single-cell RNA-sequencing and identified 4 separate clusters, 3 of which included cells with a phenotype and transcriptome consistent with that of B cell activation and proliferation. The more distant cluster corresponded to plasma cells (PCs) expressing IGHG, IGHA, and IGHE, implying prior class-switch recombination. To assess their specificity, we generated recombinant monoclonal antibodies (rAbs) from 362 PCs using a paired IgH and lgL chain expression cloning strategy. For comparison, rAbs were also generated from 296 undifferentiated CD21+CD35+ thymic B cells. The PC contingent was highly enriched in clones reactive to apoptotic cells when compared to CD21+CD35+ naïve B cells, an essential characteristic of natural antibodies. Remarkably, we identified individual PC clones reactive to some bacterial species also recognized by natural antibodies. Taken together, we demonstrate the differentiation of plasma cells reactive to apoptotic cells and common bacteria within the thymus, suggesting that thymus is a source of natural antibodies, contributing to newborn humoral immunity.
Published Version
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