Novel exosome-targeted CD4+ T cell vaccine counteracting CD4+25+ regulatory T cell-mediated immune suppression and stimulating efficient central memory CD8+ CTL responses

T cell-to-T cell Ag presentation is increasingly attracting attention. In this study, we demonstrated that active CD4(+) T (aT) cells with uptake of OVA-pulsed dendritic cell-derived exosome (EXOOVA,) express exosomal peptide/MHC class I and costimulatory molecules. These EXOOVA-uptaken (targeted) CD4(+) aT cells can stimulate CD8(+) T cell proliferation and differentiation into central memory CD8(+) CTLs and induce more efficient in vivo antitumor immunity and long-term CD8(+) T cell memory responses than OVA-pulsed dendritic cells. They can also counteract CD4(+)25(+) regulatory T cell-mediated suppression of in vitro CD8(+) T cell proliferation and in vivo CD8(+) CTL responses and antitumor immunity. We further elucidate that the EXOOVA-uptaken (targeted)CD4(+) aT cell's stimulatory effect is mediated via its IL-2 secretion and acquired exosomal CD80 costimulation and is specifically delivered to CD8(+) T cells in vivo via acquired exosomal peptide/MHC class I complexes. Therefore, EXO-targeted active CD4(+) T cell vaccine may represent a novel and highly effective vaccine strategy for inducing immune responses against not only tumors, but also other infectious diseases.