Transplants foster B cell alloimmunity by relaying extracellular vesicles to follicular dendritic cells

B cells play fundamental roles in transplant rejection. However, how allogeneic (allo)-antigens (Ags) are transported from allografts to follicular dendritic cells (FDCs) in lymphoid tissues for development of B cell responses remains unknown. We demonstrated that graft allo-Ags are relayed to FDCs via small extracellular vesicles (sEVs), which activate complement via immunoglobulin M (IgM) bound to vesicle phospholipids. Complement-opsonized allo-sEVs bind splenic marginal-zone B cells that shuttle the vesicles to FDCs, which retain and recycle the allo-sEVs so they are recognized by B cells. Accordingly, graft release of allo-sEVs promoted allo-major histocompatibility complex (MHC) accumulation in FDCs, germinal center formation, Ig switch and affinity maturation, and donor-specific antibodies, which decreased in allografts with impaired sEV secretion or when allo-Ags were delivered via disrupted sEVs. Importantly, human spleen FDCs bound allo-sEVs opsonized with human serum bearing active complement. Our findings provide insight into the mechanisms that lead to antibody-mediated rejection, for which there are no FDA-approved therapies.