T Cell Responses in Dengue Hemorrhagic Fever: Are Cross-Reactive T Cells Suboptimal?

Abstract

Dengue virus infection poses a growing public health and economic burden in a number of tropical and subtropical countries. Dengue circulates as a number of quasispecies, which can be divided by serology into four groups or serotypes. An interesting feature of Dengue, recognized over five decades ago, is that most severe cases that show hemorrhagic fever are not suffering from a primary infection. Instead, they are reinfected with a virus of different serotype. This observation poses considerable problems in vaccine design, and it is therefore imperative to gain a full understanding of the mechanisms underlying this immunological enhancement of disease. In this study, we examined a T cell epitope restricted by HLA-A*24, a major MHC class I allele, in Southeast Asia in a cohort of children admitted to a hospital with acute Dengue infection. The cytokine profiles and the degranulation capacity of T cells generated to this epitope are defined and compared across different viral serotypes. Cross-reactive Dengue-specific T cells seem to show suboptimal degranulation but high cytokine production, which may contribute to the development of the vascular leak characteristic of Dengue hemorrhagic fever.

Flow cytometric detection of degranulation reveals phenotypic heterogeneity of degranulating CMV-specific CD8+ T lymphocytes in rhesus macaques

“…Using a combination of the CD107 mobilization assay and intracellular cytokine staining, there have been limited reports of heterogeneity in the degranulating and cytokine producing properties of human CD8+ T lymphocytes responding to epitopes in HIV, CMV, and dengue virus Lacey et al, 2005;Lacey et al, 2006;Mongkolsapaya et al, 2006). Similar to our observation in rhCMV-specific CD8+ T lymphocytes, human CMV-specific CD8+ T lymphocytes targeting different epitopes showed variation in their degranulating and cytokine producing capacity (Lacey et al, 2005;Lacey et al, 2006).…”

“…This property has recently been exploited for flow-cytometric identification of CTL at the single-cell level. Simultaneous characterization of cytolytic and cytokine-secreting effector functions at the single-cell level have shed light on the functional heterogeneity of virus-specific CD8+ CTL in mice and humans Wolint et al, 2004;Lacey et al, 2005;Betts et al, 2006;Lacey et al, 2006;Mongkolsapaya et al, 2006). In this study, we have optimized the flow-cytometric technique for detection of degranulating CD8+ T lymphocytes in rhesus macaques, and used it to characterize the functional properties of rhesus cytomegalovirus (rhCMV)-specific CD8+ T lymphocytes.…”

Cytokine Factors Present in Dengue Patient Sera Induces Alterations of Junctional Proteins in Human Endothelial Cells

“…These cytokines interact directly with vascular endothelium, resulting in plasma leakage. 13,14 Although many studies have reported that the inflammatory response, cytokine storm, and activation of the complement system play a key role in the progression of severe clinical manifestation, identification of appropriate cytokine profiles, especially during the critical period of illness (defervescence stage) and its association with the progression of severe dengue, is not well established. 8,[15][16][17][18] In this study, we attempted to demonstrate the effects of cytokines in serum of DHF patients by using an in vitro model of HUVEC.…”

The Memory T Cell Response to West Nile Virus in Symptomatic Humans following Natural Infection Is Not Influenced by Age and Is Dominated by a Restricted Set of CD8+ T Cell Epitopes

“…Characterization of T cell immunity in naturally infected patients who experienced mild and severe illness following WNV infection will provide new insight into the potential role of T cells in disease outcome and pathology. Such information may also be of value to other flavivirus infections, such as dengue, where T cells have similarly been associated with protection and immunopathology (9,10).…”