Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection

Infection with one of the four dengue virus serotypes (DENV1-4) presumably leads to lifelong immunity against the infecting serotype but not against heterotypic reinfection, resulting in a greater risk of developing Dengue Hemorrhagic Fever/Dengue Shock Syndrome (DHF/DSS) during secondary infection. Both antibodies and T cell responses have been implicated in DHF/DSS pathogenesis. According to the T cell-based hypothesis termed “original antigenic sin,” secondary DENV infection is dominated by non-protective, cross-reactive T cells that elicit an aberrant immune response. The goal of our study was to compare the roles of serotype-specific and cross-reactive T cells in protection vs. pathogenesis during DENV infection in vivo. Specifically, we utilized IFN-α/βR−/− HLA*B0702 transgenic mice in the context of peptide vaccination with relevant human CD8 T cell epitopes. IFN-α/βR−/− HLA*B0702 transgenic mice were immunized with DENV serotype 2 (DENV2)-specific epitopes or variants found in any of the other three serotypes (DENV1, DENV3 or DENV4), followed by challenge with DENV. Although cross-reactive T cell responses were lower than responses elicited by serotype-specific T cells, immunization with either serotype-specific or variant peptide epitopes enhanced viral clearance, demonstrating that both serotype-specific and cross-reactive T cells can contribute to protection in vivo against DENV infection.
Highlights • Serotype-cross-reactive CD8 T cells elicit a polyfunctional immune response similar to the response elicited by serotype-specific CD8 T cells. • Serotype cross-reactive CD8 T cells play a role in protection against DENV infection in a HLA-B*0702 Transgenic IFN-α/βR−/− mouse model. There are four major subtypes (serotypes) of the mosquito-borne Dengue virus. Infection with a first serotype is generally asymptomatic, but secondary infection with a different serotype is capable of causing severe disease. T cells previously exposed to a first serotype and which produce an immune response to a second serotype are said to be cross-reactive. Using a mouse model engineered with human T cell features, we characterized the cross-reactive T cell response to live dengue virus serotypes and viral protein fragments. Our results suggested cross-reactive T cells contribute to control of and protection against infection by a second dengue serotype, rather than leading to more severe disease.