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.
Hao
Siguo
S
Research Unit, Division of Health Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan, Canada.
Yuan
Jinying
J
Xiang
Jim
J
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D008545:Melanoma / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D008934:Mitogens / Q000494:pharmacology; D010047:Ovalbumin / Q000276:immunology; D010455:Peptides / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013997:Time Factors
D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D019013:CD40 Antigens; D019496:Cancer Vaccines; D015395:Histocompatibility Antigens Class I; D008934:Mitogens; D010455:Peptides; D003208:Concanavalin A; D010047:Ovalbumin