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

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-γ, TNF-α, MIP-1β, 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.

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).…”

Timing of CD8+ T Cell Responses in Relation to Commencement of Capillary Leakage in Children with Dengue

“…Similarly, CD8 + T cells specific for the dominant HLA-A p 11-restricted epitope NS3 [133][134][135][136][137][138][139][140][141][142] were present only at very low frequency during the febrile phase in Thai children, but were readily detected in early convalescence (21). Other studies to characterize DENV-epitope-specific T cell responses have used PBMCs collected in late convalescence and so it is difficult to know whether these findings can be extrapolated to the febrile phase (22,23).…”

Immunodominance Changes as a Function of the Infecting Dengue Virus Serotype and Primary versus Secondary Infection

“…To enable these studies, we first sought to experimentally define a homology threshold associated with cross-reactivity at the T cell level. The phenomenon of T cell-mediated crossreactivity between various serotypes has been the subject of much discussion in the context of dengue virus infection (11,12,36,37), but a definition of the threshold for cross-reactivity broadly applicable to large number of epitopes has not been experimentally addressed.…”

“…According to this hypothesis, T cells induced by a primary infection dominate the secondary heterologous infection but are of lower efficacy in clearing the infection (9,10). Peptide variants derived from the secondary infection serotype can induce a response that is qualitatively different from the response induced by the original antigen, such as inducing a different pattern of cytokine production, and thus contribute to immunopathogenesis of severe disease (11,12). However, this hy-pothesis is in conflict with the observation that heterologous T cell responses are not always needed to produce DHF in infants.…”