Identification and immunogenicity of two new HLA-A*0201-restricted CD8+ T-cell epitopes on dengue NS1 protein.
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.
Key Laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Jiang
J
Tian
Gucheng
G
Zeng
Xianwu
X
Pang
Mifang
M
Liang
Junmei
J
Zhou
Danyun
D
Fang
Yan
Y
Liu
Dexin
D
Li
Lifang
L
Jiang
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000956:Antigens, Viral / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D003715:Dengue / Q000276:immunology; D003716:Dengue Virus / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D037181:Lectins, C-Type / Q000032:analysis; D017493:Leukocyte Common Antigens; D051379:Mice; D008822:Mice, Transgenic; D054353:Perforin / Q000096:biosynthesis; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D007371:Interferon-gamma; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D054353:Perforin; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; D000099192:CD69 Antigens; C435939:HLA-A*02:01 antigen