The Role of Heterotypic DENV-specific CD8+ T Lymphocytes in an Immunocompetent Mouse Model of Secondary Dengue Virus Infection

Dengue is the most prevalent arthropod-borne viral disease worldwide and is caused by the four dengue virus serotypes (DENV-1-4). Sequential heterologous DENV infections can be associated with severe disease manifestations. Here, we present an immunocompetent mouse model of secondary DENV infection using non mouseadapted DENV strains to investigate the pathogenesis of severe dengue disease. C57BL/6 mice infected sequentiallywith DENV-1 (strain Puerto Rico/94) and DENV-2 (strain Tonga/74) developed lowplatelet counts, internal hemorrhages, and increase of liver enzymes. Cross-reactive CD8(+) T lymphocyteswere found to be necessary and sufficient for signs of severe disease by adoptively transferring of DENV-1-immune CD8(+) T lymphocytes before DENV-2 challenge. Disease signswere associatedwith production of tumor necrosis factor (TNF)-a and elevated cytotoxicity displayed by heterotypic anti-DENV-1 CD8(+) T lymphocytes. These findings highlight the critical role of heterotypic anti-DENV CD8(+) T lymphocytes in manifestations of severe dengue disease.(C) 2017 The Authors. Published by Elsevier B. V.