Nonspecific CD4 + T cells with uptake of antigen‐specific dendritic cell‐released exosomes stimulate antigen‐specific CD8 + CTL responses and long‐term T cell memory

Dendritic cell (DC) and DC‐derived exosomes (EXO) have been used extensively for tumor vaccination. However, its therapeutic efficiency is limited to only production of prophylactic immunity against tumors. T cells can uptake DC‐released EXO. However, the functional effect of transferred exosomal molecules on T cells is unclear. In this study, we demonstrated that OVA protein‐pulsed DC‐derived EXO (EXO OVA ) can be taken up by Con A‐stimulated, nonspecific CD4 + T cells derived from wild‐type C57BL/6 mice. The active EXO‐uptaken CD4 + T cells (aT EXO ), expressing acquired exosomal MHC I/OVA I peptide (pMHC I) complexes and costimulatory CD40 and CD80 molecules, can act as APCs capable of stimulating OVA‐specific CD8 + T cell proliferation in vitro and in vivo and inducing efficient CD4 + Th cell‐independent CD8 + CTL responses in vivo. The EXO OVA ‐uptaken CD4 + aT EXO cell vaccine induces much more efficient CD8 + T cell responses and immunity against challenge of OVA‐transfected BL6‐10 melanoma cells expressing OVA in wild‐type C57BL/6 mice than EXO OVA . The in vivo stimulatory effect of the CD4 + aT EXO cell to CD8 + T cell responses is mediated and targeted by its CD40 ligand signaling/acquired exosomal CD80 and pMHC I complexes, respectively. In addition, CD4 + aT EXO vaccine stimulates a long‐term, OVA‐specific CD8 + T cell memory. Therefore, the EXO OVA ‐uptaken CD4 + T cells may represent a new, effective, EXO‐based vaccine strategy in induction of immune responses against tumors and other infectious diseases.