Identification and immunogenicity of two new HLA-A*0201-restricted CD8 + T-cell epitopes on dengue NS1 protein

摘要

Immunopathogenesis of dengue virus (DEN) infection remains poorly studied. Identification and characterization of human CD8 + T-cell epitopes on DEN are necessary for a better understanding of the immunopathogenesis of dengue infection and would facilitate the development of immunotherapy and vaccines to protect from dengue infection. Here, we identified two new HLA-A*0201-restricted CD8 + T-cell epitopes, DEN-4 NS1 990-998 and DEN-4 NS1 997-1005 that are conserved in three or four major DEN serotypes, respectively. Unexpectedly, we found that immunization of HLA-A*0201 transgenic mice with DEN-4 NS1 990-998 or DEN-4 NS1 997-1005 epitope peptide induced de novo synthesis of tumor necrosis factor (TNF)-α and IFN-γ, two important pro-inflammatory molecules that are hard to be detected directly without in vitro antigenic re-stimulation. Importantly, we demonstrated that CD8 + T cells specifically activated by DEN-4 NS1 990-998 or DEN-4 NS1 997-1005 epitope peptide induced de novo synthesis of perforin. Furthermore, we observed that DEN-4 NS1 990-998 or DEN-4 NS1 997-1005-specific CD8 + T cells capable of producing large amounts of perforin, TNF-α and IFN-γ preferentially displayed CD27 +CD45RA -, but not CD27 -CD45RA +, phenotypes. This study, therefore, suggested the importance of synergistic effects of pro-inflammatory cytokines and cytotoxic molecules which were produced by dengue-specific CD8 + T cells in immunopathogenesis or anti-dengue immunity during dengue infection.