The ultimate goal of antitumor vaccines is to develop memory CD8＋ cytotoxic T lymphocytes （CTLs）, which are critical mediators of antitumor immunity. We previously demonstrated that the ovalbumin （OVA）-specific ...The ultimate goal of antitumor vaccines is to develop memory CD8＋ cytotoxic T lymphocytes （CTLs）, which are critical mediators of antitumor immunity. We previously demonstrated that the ovalbumin （OVA）-specific CD4＋ T cell-based （OVA-TExo） vaccine generated using OVA-pulsed dendritic cell （DCovA）-released exosomes （EXOovA） stimulate CTL responses via IL-2 and costimulatory CD80 signaling. To assess the potential involvement of other costimulatory pathways and to define the key constituent of costimulation for memory CTL development, we first immunized wild-type （WT） C57BIJ6 and gene-knockout mice with WT CD4~ OVA-TExo cells or OVA-TExo cells with various molecular deficiencies. We then assessed OVA-specific primary and recall CTL responses using PE-H-2Kb/ 0VA257_264 tetramer and FITC-anti-CD8 antibody staining by flow cytometry. We also examined antitumor immunity against the OVA-expressing B16 melanoma cell line BL6-1OovA. We demonstrated that CD4＋ OVA-TExo cells stimulated more efficient CTL responses compared to DCovA. By assessing primary and recall CTL responses in mice immunized with OVA-TExo or with OVA-TExo lacking the costimulatory molecules CD4OL, 4-1BBL or OX4OL, we demonstrated that these costimulatory signals are dispensable for CTL priming by OVA-TExo. Interestingly, CD4OL, but not 4-1BBL or OX4OL, plays a crucial role in the development of functional memory CTLs against BL6-1OovA tumors. Overall, this work suggests that a novel CD4＋ T cell-based vaccine that is capable of stimulating long-term functional CTL memory via CD40L signaling may represent a novel, efficient approach to antitumor vaccination.展开更多
文摘The ultimate goal of antitumor vaccines is to develop memory CD8＋ cytotoxic T lymphocytes （CTLs）, which are critical mediators of antitumor immunity. We previously demonstrated that the ovalbumin （OVA）-specific CD4＋ T cell-based （OVA-TExo） vaccine generated using OVA-pulsed dendritic cell （DCovA）-released exosomes （EXOovA） stimulate CTL responses via IL-2 and costimulatory CD80 signaling. To assess the potential involvement of other costimulatory pathways and to define the key constituent of costimulation for memory CTL development, we first immunized wild-type （WT） C57BIJ6 and gene-knockout mice with WT CD4~ OVA-TExo cells or OVA-TExo cells with various molecular deficiencies. We then assessed OVA-specific primary and recall CTL responses using PE-H-2Kb/ 0VA257_264 tetramer and FITC-anti-CD8 antibody staining by flow cytometry. We also examined antitumor immunity against the OVA-expressing B16 melanoma cell line BL6-1OovA. We demonstrated that CD4＋ OVA-TExo cells stimulated more efficient CTL responses compared to DCovA. By assessing primary and recall CTL responses in mice immunized with OVA-TExo or with OVA-TExo lacking the costimulatory molecules CD4OL, 4-1BBL or OX4OL, we demonstrated that these costimulatory signals are dispensable for CTL priming by OVA-TExo. Interestingly, CD4OL, but not 4-1BBL or OX4OL, plays a crucial role in the development of functional memory CTLs against BL6-1OovA tumors. Overall, this work suggests that a novel CD4＋ T cell-based vaccine that is capable of stimulating long-term functional CTL memory via CD40L signaling may represent a novel, efficient approach to antitumor vaccination.
