Abstract
BackgroundPrevious studies of T cell activation in dengue infection have focused on restriction of specific T cell receptors (TCRs) and classical MHC molecules. However, bystander T cell activation, which is TCR independent, occurs via cytokines in other viral infections, both in vitro and in vivo, and enables T cells to bypass certain control checkpoints. Moreover, clinical and pathological evidence has pointed to cytokines as the mediators of dengue disease severity. Therefore, we investigated bystander T cell induction by dengue viral antigen.ResultsWhole blood samples from 55 Thai schoolchildren aged 13-14 years were assayed for in vitro interferon-gamma (IFN-γ) induction in response to inactivated dengue serotype 2 antigen (Den2). The contribution of TCR-dependent and independent pathways was tested by treatment with cyclosporin A (CsA), which inhibits TCR-dependent activation of T cells. ELISA results revealed that approximately 72% of IFN-γ production occurred via the TCR-dependent pathway. The major IFN-γ sources were natural killer (NK) (mean ± SE = 55.2 ± 3.3), CD4+T (24.5 ± 3.3) and CD8+T cells (17.9 ± 1.5), respectively, as demonstrated by four-color flow cytometry. Interestingly, in addition to these cells, we found CsA-resistant IFN-γ producing T cells (CD4+T = 26.9 ± 3.6% and CD8+T = 20.3 ± 2.1%) implying the existence of activated bystander T cells in response to dengue antigen in vitro. These bystander CD4+ and CD8+T cells had similar kinetics to NK cells, appeared after 12 h and were inhibited by anti-IL-12 neutralization indicating cytokine involvement.ConclusionsThis study described immune cell profiles and highlighted bystander T cell activation in response to dengue viral antigens of healthy people in an endemic area. Further studies on bystander T cell activation in dengue viral infection may reveal the immune mechanisms that protect or enhance pathogenesis of secondary dengue infection.
Highlights
Previous studies of T cell activation in dengue infection have focused on restriction of specific T cell receptors (TCRs) and classical MHC molecules
Bystander T cell activity was demonstrated by resistance to cyclosporin A (CsA), which is a substance known to inhibit T cell activation via the TCR-dependent pathway [9,19,20] In addition, we described the kinetics of bystander T cells and cytokines involved in IFNg-derived T cell activation
Blood samples from 55 healthy Thai schoolchildren aged 13-14 years were co-cultured with control stimulators (medium, phytohemagglutinin (PHA) and a combination of IL-12 plus IL-15 cytokines) or dengue serotype 2 antigen (Den2) in the absence or presence of CsA for 48 h
Summary
Previous studies of T cell activation in dengue infection have focused on restriction of specific T cell receptors (TCRs) and classical MHC molecules. Bystander T cell activation, which is TCR independent, occurs via cytokines in other viral infections, both in vitro and in vivo, and enables T cells to bypass certain control checkpoints. The mechanisms of T cell activation are mostly focused on the classical pathway, that is activation via binding of specific T cell receptors (TCRs) and MHC molecules [6,7]. Previous studies have revealed that a storm of pro-inflammatory cytokines is released during acute infection [18]. These observations suggest that bystander T cell activation might possibly occur in dengue infection
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