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.