Setliff, I. et al. Cell 179, 1636–1646 (2019).

B-cell receptor (BCR) sequencing offers an important approach for examining immune responses to infection. Antigen-specific BCRs are often sequenced following single-cell sorting with antigen baits. However, this strategy is low throughput. Setliff et al. developed LIBRA-seq for linking BCR sequences to antigen specificity via next-generation sequencing. Single B cells are mixed with a set of DNA-barcoded antigens that are used to sort antigen-positive B cells. Then the sorted B cells are encapsulated with oligonucleotide-labeled beads for indexing both BCR transcripts and antigen barcodes, which allows sequencing both the antigen barcodes and BCR sequences, thus providing a direct readout of BCR–antigen binding interactions. This transformation to sequencing readouts allows high-throughput mapping of BCR sequences to antigen specificity. The researchers applied LIBRA-seq to peripheral blood mononuclear cells collected from two people infected with HIV and identified HIV- and influenza-specific antibodies.