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 gamma (IFN gamma), tumor necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1 beta (MIP-1 beta), 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 IFN gamma > TNF-alpha > MIP-beta > CD107a, T cells of those with DHF predominantly expressed CD107a > MIP-1 beta > IFN gamma > TNF-alpha. Overall production of IFN gamma or TNF-alpha 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.