Human CD8<>+<> T-Cell Responses Against the 4 Dengue Virus Serotypes Are Associated with Distinct Patterns of Protein Targets

Abstract

All 4 dengue virus (DENV) serotypes are now simultaneously circulating worldwide and responsible for up to 400 million human infections each year. Previous studies of CD8<>+<> T-cell responses in HLA-transgenic mice and human vaccinees demonstrated that the hierarchy of immunodominance among structural versus nonstructural proteins differs as a function of the infecting serotype. This led to the hypothesis that there are intrinsic differences in the serotype-specific reactivity of CD8<>+<> T-cell responses. Methods. We tested this hypothesis by analyzing serotype-specific CD8<>+<> T-cell reactivity in naturally infected human donors from Sri Lanka and Nicaragua, using ex vivo interferon γ-specific enzyme-linked immunosorbent spot assays. Results. Remarkably similar and clear serotype-specific patterns of immunodominance in both cohorts were identified. Pooling of epitopes that accounted for 90% of the interferon γ response in both cohorts resulted in a global epitope pool. Its reactivity was confirmed in naturally infected donors from Brazil, demonstrating its global applicability. Conclusions. This study provides new insight into differential serotype-specific immunogenicity of DENV proteins. It further provides a potentially valuable tool for future investigations of CD8<>+<> T-cell responses in the typically small sample volumes available from patients with acute fever and children without requiring prior knowledge of either infecting DENV serotype or HLA type.