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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: 5.36). 04/2006; 176(5):2817-24. DOI: 10.4049/jimmunol.176.5.2817
Source: PubMed

ABSTRACT 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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    • "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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    • "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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    Cell and Tissue Research 03/2014; 355(3). DOI:10.1007/s00441-014-1841-9 · 3.33 Impact Factor
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    • "In recent years, research studies have revealed many DV-specific CD8+ T-cell epitopes. These are mostly located in E, NS3, NS4a, NS4b, NS5 and restricted by HLA-A2, A11, A24, B7, B55, B65 [9,11,12,17,20-23]. Lund et al [22] and Weiskopf et al [23] used HLA-A*0201 transgenic mice and identified several D1V- and D2V-specific HLA-A*0201-retricted epitopes, respectively. "
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