Association of dengue virus-specific polyfunctional T-cell responses with clinical disease severity in acute dengue infection.

INTRODUCTION: Although the role of dengue virus (DENV)-specific T cells in the pathogenesis of acute dengue infection is emerging, the functionality of virus-specific T cells associated with milder clinical disease has not been well studied. We sought to investigate how the functionality of DENV-NS3 and DENV-NS5 protein-specific T cells differ in patients with dengue fever (DF) and dengue hemorrhagic fever (DHF). METHODS: Using intracellular cytokine assays, we assessed the production of interferon γ (IFNγ), tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1β (MIP-1β), and CD107a expression in adult patients with acute DF (n = 21) and DHF (n = 22). RESULTS: Quadruple cytokine-producing, polyfunctional DENV-NS3- and DENV-NS5-specific T cells were more frequent in those with DF when compared to those with DHF. While DENV-NS3- and DENV-NS5-specific T cells in patients with DF expressed IFNγ > TNF-α > MIP-β > CD107a, T cells of those with DHF predominantly expressed CD107a > MIP-1β > IFNγ > TNF-α. Overall production of IFNγ or TNF-α by DENV-NS3- and DENV-NS5-specific T cells was significantly higher in patients with DF. The majority of NS3-specific T cells in patients with DF (78.6%) and DHF (68.9%) were single-cytokine producers; 76.6% of DENV-NS5-specific T cells in those with DF and 77.1% of those with DHF, produced only a single cytokine. However, no significant association was found with polyfunctional T-cell responses and the degree of viraemia. CONCLUSIONS: Our results suggest that the functional phenotype of DENV-specific T cells are likely to associate with clinical disease severity.