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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    • "Stimulation with heterologous serotype peptide resulted in more TNF-producing cells than IFN producers relative to stimulation with homologous peptides, suggesting differential functional phenotypes amongst these cell populations that are dependent on the type of antigenic stimulation. This repeats a theme also evident in studies of CD8+ T cells, that partial peptide agonists elicit a diverse range of functional phenotypes in cross-reactive T cells [15]. In a mouse model, Yauch et al. [16] identified that DENV2-specific CD4+ T cells were of a Th1 phenotype and could mediate in vivo cytotoxicity and that immunization with dominant CD4+ T cell epitopes led to enhance viral clearance. "
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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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