Invariant NKT Cell Response to Dengue Virus Infection in Human

Abstract

BackgroundDengue viral infection is a global health threat without vaccine or specific treatment. The clinical outcome varies from asymptomatic, mild dengue fever (DF) to severe dengue hemorrhagic fever (DHF). While adaptive immune responses were found to be detrimental in the dengue pathogenesis, the roles of earlier innate events remain largely uninvestigated. Invariant natural killer T (iNKT) cells represent innate-like T cells that could dictate subsequent adaptive response but their role in human dengue virus infection is not known. We hypothesized that iNKT cells play a role in human dengue infection.MethodsBlood samples from a well-characterized cohort of children with DF, DHF, in comparison to non-dengue febrile illness (OFI) and healthy controls at various time points were studied. iNKT cells activation were analyzed by the expression of CD69 by flow cytometry. Their cytokine production was then analyzed after α-GalCer stimulation. Further, the CD1d expression on monocytes, and CD69 expression on conventional T cells were measured.ResultsiNKT cells were activated during acute dengue infection. The level of iNKT cell activation associates with the disease severity. Furthermore, these iNKT cells had altered functional response to subsequent ex vivo stimulation with α-GalCer. Moreover, during acute dengue infection, monocytic CD1d expression was also upregulated and conventional T cells also became activated.ConclusioniNKT cells might play an early and critical role in the pathogenesis of severe dengue viral infection in human. Targeting iNKT cells and CD1d serve as a potential therapeutic strategy for severe dengue infection in the future.

Expansion of highly activated invariant natural killer T cells with altered phenotype in acute dengue infection

“…This is in contrast to a previous study in children which showed that the frequency of iNKT cells in patients was similar to healthy donors [12]. Although the reasons for this difference in not clear, it is possible that the iNKT cell frequencies are different in adults and children.…”

“…Although not significant, we observed that patients with DF had a higher frequency of iNKT cells and also higher iNKT cell numbers. In a previous study, it was shown that patients with DF produced more IFN-g than IL-4 when compared to those with DHF [12]. Therefore, iNKT cells could be playing a significant role in anti-viral defences against the DENV.…”

“…In humans, the T cell receptor of iNKT cells comprises the alpha chain Va24-Ja18, which is paired with Vb11 [10]. The role of iNKT cells has been investigated in many viral infections, such as HIV, herpes simplex virus (HSV), hepatitis [10], influenza [11] and more recently in dengue infection [12]. In dengue infection, iNKT cells were shown to be highly activated, and were associated with clinical disease severity [12].…”

“…The role of iNKT cells has been investigated in many viral infections, such as HIV, herpes simplex virus (HSV), hepatitis [10], influenza [11] and more recently in dengue infection [12]. In dengue infection, iNKT cells were shown to be highly activated, and were associated with clinical disease severity [12]. Interestingly, the functionality of iNKT cells in patients with milder forms of dengue such as DF was found to be different to that in patients with DHF, with iNKT cells of patients with DF producing more IFN-g than interleukin (IL)-4 [12].…”

“…In dengue infection, iNKT cells were shown to be highly activated, and were associated with clinical disease severity [12]. Interestingly, the functionality of iNKT cells in patients with milder forms of dengue such as DF was found to be different to that in patients with DHF, with iNKT cells of patients with DF producing more IFN-g than interleukin (IL)-4 [12].…”