Exosome-primed T cell immunity is facilitated by complement activation.

Extracellular vesicles (EVs) contain proteins, lipids, and nucleic acids from their cells of origin. By delivering these cargos to distant acceptor cells, EVs modulate many biologic processes, including adaptive immunity. Following transplantation, EV's expressing donor major histocompatibility complexes bind to host dendritic cells (DCs), permitting donor major histocompatibility complexes expression by recipient DCs and priming antidonor T cell responses. The mechanisms through which circulating EVs bind DCs are poorly understood. The complement system opsonizes pathogens and damaged cells and enhances subsequent recognition by antigen-presenting cells through surface-expressed complement receptors. Here, we newly show that complement opsonization of graft-released EVs augments their binding to recipient DCs in a CD11c-dependent manner. Enhanced delivery of donor antigen by EVs induces antidonor T cell responses and graft rejection, which can be mitigated by pharmacologic inhibition of complement activation. Our findings reveal a previously unrecognized mechanism linking complement activation to EV function with important implications for T cell immunity.