Dengue Virus-Reactive CD8+ T Cells Display Quantitative and Qualitative Differences in Their Response to Variant Epitopes of Heterologous Viral Serotypes

Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, Worcester, MA 01655, USA.
The Journal of Immunology (Impact Factor: 4.92). 04/2006; 176(5):2817-24. DOI: 10.4049/jimmunol.176.5.2817
Source: PubMed


Reactivation of serotype cross-reactive CD8+ memory T lymphocytes is thought to contribute to the immunopathogenesis of dengue disease during secondary infection by a heterologous serotype. Using cytokine flow cytometry, we have defined four novel HLA-A*02-restricted dengue viral epitopes recognized by up to 1.5% of circulating CD8+ T cells in four donors after primary vaccination. All four donors had the highest cytokine response to the epitope NS4b 2353. We also studied the effect of sequence differences in heterologous dengue serotypes on dengue-reactive CD8+ memory T cell cytokine and proliferative responses. The D3 variant of a different NS4b epitope 2423 and the D2 variant of the NS4a epitope 2148 induced the largest cytokine response, compared with their respective heterologous sequences in all donors regardless of the primary vaccination serotype. Stimulation with variant peptides also altered the relative frequencies of the various subsets of cells that expressed IFN-gamma, TNF-alpha, MIP-1beta, and combinations of these cytokines. These results indicate that the prior infection history of the individual as well as the serotypes of the primary and heterologous secondary viruses influence the nature of the secondary response. These differences in the effector functions of serotype cross-reactive memory T cells induced by heterologous variant epitopes, which are both quantitative and qualitative, may contribute to the clinical outcome of secondary dengue infection.

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    • "The relevance of cellular immune responses has also been extensively studied in the control of DENV infection (Bäck and Lundkvist, 2013; Bashyam et al., 2006; Han et al., 2012; Kurane et al., 1991; Yauch et al., 2010; Yoshida et al., 2013; Zellweger et al., 2013). CD4 þ and CD8 þ T lymphocytes specific for DENV antigens have been demonstrated to be important in controlling virus spread and intracellular replication (Gil et al., 2009; Rivino et al., 2013; Yoshida et al., 2013). "
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    ABSTRACT: Generating neutralizing antibodies have been considered a prerequisite to control dengue virus (DENV) infection. However, T lymphocytes have also been shown to be important in a protective immune state. In order to investigate the contribution of both humoral and cellular immune responses in DENV immunity, we used an experimental model in which a non-lethal DENV2 strain (ACS46) is used to intracranially prime Balb/C mice which develop protective immunity against a lethal DENV2 strain (JHA1). Primed mice generated envelope-specific antibodies and CD8(+) T cell responses targeting mainly non-structural proteins. Immune sera from protected mice did not confer passive protection to naïve mice challenged with the JHA1 strain. In contrast, depletion of CD4(+) and CD8(+) T lymphocytes significantly reduced survival of ACS46-primed mice challenged with the JHA1 strain. Collectively, results presented in this study show that a cellular immune response targeting non-structural proteins are a promising way in vaccine development against dengue.
    Virology 01/2016; 487:41-49. DOI:10.1016/j.virol.2015.10.006 · 3.32 Impact Factor
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    • "Furthermore, IP-10 and RANTES were up-regulated in other DENV-infected human cell lines, including the K562/Jurkat/A549 cell lines (Chen et al., 2008; Fink et al., 2007). In addition, MIP-1␤, which was up-regulated in DENV-infected HEK293 cells, was shown to be associated with both dengue severity and disease outcome (Bashyam et al., 2006; Bozza et al., 2008). Surprisingly, IL-6 and IL-10 mRNA expression were down-regulated in this study. "
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    ABSTRACT: Dengue virus (DENV) infection associates with renal disorders. Patients with dengue hemorrhagic fever and acute kidney injury have a high mortality rate. Increased levels of cytokines may contribute to the pathogenesis of DENV-induced kidney injury. Currently, molecular mechanisms how DENV induces kidney cell injury has not been thoroughly investigated. Excessive cytokine production may involve in this process. Using human cytokine RT(2) Profiler PCR array, 14 genes including IP-10, RANTES, IL-8, CXCL-9 and MIP-1β were up-regulated more than 2folds in DENV-infected HEK 293 cells compared to that of mock-infected HEK 293 cells. In the present study, RANTES was suppressed by the NF-κB inhibitor, compound A (CpdA), in DENV-infected HEK 293 cells implying the role of NF-κB in RANTES expression. Chromatin immunoprecipitation (ChIP) assay showed that NF-κB binds more efficiently to its binding sites on the RANTES promoter in NS5-transfected HEK 293 cells than in HEK 293 cells expressing the vector lacking NS5. To further examine whether the NS5-activated RANTES promoter is mediated through NF-κB, the two NF-κB binding sites on the RANTES promoter were mutated and this promoter was coupled to the luciferase cDNA. The result showed that when both binding sites of NF-κB in the RANTES promoter were mutated, the ability of NS5 to induce the luciferase activity was significantly decreased. Therefore, DENV NS5 activates RANTES production by increasing NF-κB binding to its binding sites on the RANTES promoter. Copyright © 2014 Elsevier B.V. All rights reserved.
    Virus Research 12/2014; 197. DOI:10.1016/j.virusres.2014.12.007 · 2.32 Impact Factor
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    • "Interestingly, cross-reactive memory T cells were preferentially expanded during a secondary infection. Functional analyses of these cross-reactive T cells have demonstrated distinct patterns of cytokine production upon activation by epitope peptides corresponding to the amino acid sequences found in the infecting or previously exposed DENV (Bashyam et al. 2006; Friberg et al. 2011; Mangada and Rothman 2005). Ex vivo analyses of T cells from dengue patients revealed decreased expression of degranulation marker (a marker for cytolytic activity) and increased cytokine production when cross-reactive memory T cells were stimulated with epitope peptides of the infecting DENV serotype (Mongkolsapaya et al. 2006). "
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    ABSTRACT: Viral hemorrhagic diseases are a group of systemic viral infections with worldwide distribution and are significant causes of global mortality and morbidity. The hallmarks of viral hemorrhagic fevers are plasma leakage, thrombocytopenia, coagulopathy and hemorrhagic manifestations. The molecular mechanisms leading to plasma leakage in viral hemorrhagic fevers are not well understood. A common theme has emerged in which a complex interplay between pathogens, host immune response, and endothelial cells leads to the activation of endothelial cells and perturbation of barrier integrity. In this article, two clinically distinct viral hemorrhagic fevers caused by dengue viruses and hantaviruses are discussed to highlight their similarities and differences that may provide insights into the pathogenesis and therapeutic approach.
    Cell and Tissue Research 03/2014; 355(3). DOI:10.1007/s00441-014-1841-9 · 3.57 Impact Factor
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