Abstract
IntroductionAlthough 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).MethodsUsing 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).ResultsQuadruple 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.ConclusionsOur results suggest that the functional phenotype of DENV‐specific T cells are likely to associate with clinical disease severity.
Highlights
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
While DENV–NS3‐specific T cells that produced a combination of CD107a/interferon γ (IFNγ)/macrophage inflammatory protein‐1β (MIP‐1β) were significantly higher in patients with dengue hemorrhagic fever (DHF) (P = .049), DENV–NS3‐specific T cells that produced tumor necrosis factor‐α (TNF‐α) alone was significantly higher (P = .02) in patients with dengue fever (DF) (Figure 2A)
We have shown that quadruple cytokine‐/ effector‐expressing, polyfunctional DENV–NS3‐ and DENV–NS5‐specific T cells were more frequent in those with DF when compared to those with DHF
Summary
Dengue viral infections affect approximately 390 million individuals annually, of which 96 million infections manifest as apparent dengue infections.[1]. There is still some controversy regarding the role of T cells in the pathogenesis of dengue infection, more recent studies have shown that DENV‐specific T cells are likely to have a protective role.[7,8,9,10] Recently, we reported that patients with DF had significantly higher DENV‐specific T‐cell responses than those with more severe forms of illness, which appeared very early in illness.[11] we found that the magnitude of the DENV‐specific T‐cell response inversely correlated with the degree of viraemia, further suggesting that T cells have a protective role in acute dengue.[11]. | 277 associated with protection.[7,9] We observed that individuals who were naturally infected with the DENV resulting in either inapparent or a severe dengue infection had the same magnitude of DENV‐specific T‐ cell responses, they differed in functionality. While many studies have been carried out to elucidate the functionality of T‐cell responses in dengue, these have been limited to studying T‐cell specific for particular HLA types by using tetramers/pentamers.[10,20] As the functionality of DENV‐specific T cells in acute dengue have not been assessed previously in relation to clinical disease severity and resolution of viraemia, we sought to determine whether polyfunctional CD8+ T‐cell responses to DENV were associated with milder disease and early resolution of viraemia
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