Lamprey and hagfish VLRB signalling complex VLRB-GPIbβ-GPIX originates from lymphocyte-specific duplication of a platelet adhesion module

Unlike jawed vertebrates relying on Ig-based adaptive immunity, jawless vertebrates utilize variable lymphocyte receptors (VLR) for antigen recognition. Despite extensive studies into VLR diversity and antigen recognition, how VLR engagement activates lymphocytes remains unexplored. Integrating single-cell and full-length transcriptomic data of lamprey and hagfish with functional studies, we identify a VLRB cell-specific tripartite VLRB-GPIbβ-1-GPIX-1 complex transducing activation signals via an ITAM motif in GPIbβ-1. Phylogenetic reconstruction reveals its origin from lineage-specific duplication of ancestral platelet GPIb-IX complex in agnathans, yielding two functionally divergent paralogs retained in thrombocytes or co-opted by VLRB lymphocytes. Transcriptional profiling demonstrates BHLHE41 and FOS as potential regulators of complex-expression. scRNA-seq reveals that VLRB cells, analogous to mammalian B cells, transition from pre-activated to post-activated states with proliferative, plasma cell-like features and VLRB complex up-regulation. Collectively, these findings reveal repurposing of a platelet-adhesion module into a VLRB cell-specific signalosome, unveiling a missing link in VLR-mediated adaptive immunity. The jawless vertebrate antigen receptor VLRB functions analogously to the B cell receptor, despite bearing no structural similarity to it. Here the authors identify the signalling complex downstream of VLRB and show that the origin of the genes encoding the signalosome is an ancient platelet unit that has been duplicated in the lymphocyte lineage.