Phosphatidylserine-positive extracellular vesicles boost effector CD8⁺ T cell responses during viral infection

CD8⁺ T cells are crucial for the clearance of viral infections. During the acute phase, proinflammatory conditions increase the amount of circulating phosphatidylserine⁺ (PS) extracellular vesicles (EVs). These EVs interact especially with CD8⁺ T cells; however, it remains unclear whether they can actively modulate CD8⁺ T cell responses. In this study, we have developed a method to analyze cell-bound PS⁺ EVs and their target cells in vivo. We show that EV⁺ cell abundance increases during viral infection and that EVs preferentially bind to activated, but not naive, CD8⁺ T cells. Superresolution imaging revealed that PS⁺ EVs attach to clusters of CD8 molecules on the T cell surface. Furthermore, EV-binding induces antigen (Ag)-specific TCR signaling and increased nuclear translocation of the transcription factor Nuclear factor of activated T-cells (NFATc1) in vivo. EV-decorated but not EV-free CD8⁺ T cells are enriched for gene signatures associated with T-cell receptor signaling, early effector differentiation, and proliferation. Our data thus demonstrate that PS⁺ EVs provide Ag-specific adjuvant effects to activated CD8⁺ T cells in vivo.