Immunodominant T-cell responses to dengue virus NS3 are associated with DHF - PubMed (original) (raw)
Immunodominant T-cell responses to dengue virus NS3 are associated with DHF
Thaneeya Duangchinda et al. Proc Natl Acad Sci U S A. 2010.
Abstract
Dengue infections are increasing at an alarming rate in many tropical and subtropical countries, where epidemics can put health care systems under extreme pressure. The more severe infections lead to dengue hemorrhagic fever (DHF), which can be life threatening. A variety of viral and host factors have been associated with the severity of dengue infections. Because secondary dengue infection is more commonly associated with DHF than primary infections, the acquired immune response to dengue, both B cells and T cells have been implicated. In this study, we set out to study T-cell responses across the entire dengue virus proteome and to see whether these were related to disease severity in a cohort of dengue-infected children from Thailand. Robust responses were observed in most infected individuals against most viral proteins. Responses to NS3 were the most frequent, and there was a very strong association between the magnitude of the response and disease severity. Furthermore, in DHF, cytokine-high CD107a-negative cells predominated.
Conflict of interest statement
The authors declare no conflict of interest.
Figures
Fig. 1.
T-cell responses to the dengue proteome. Shown are representative plots for CD4+ and CD8+ T-cell subsets from PBMC stimulated with peptide pools covering the dengue proteome. (A) Gating strategy. Representative sets of responses for CD4 (B) and CD8 (C) T cells.
Fig. 2.
Breadth and magnitude of dengue specific T-cell responses. (A) T-cell responses against dengue virus were broad; the numbers above the bars represent the number of responding patients. (B) Magnitude of the responses to the peptide pools in the DF and DHF patient groups. (C) Sum of responses to all peptide pools for each patient. Differences between the two groups were tested by using the nonparametric two tailed Mann–Whitney test. Asterisks indicated P values: *P < 0.05; **P < 0.005; ***P < 0.0005.
Fig. 3.
NS3-specific responses in primary and secondary infections. (A) PBMC were stimulated with NS3 from the serotype of their current infection. Total responding cells (CD107a or IFN-γ or TNF-α) or individual responses to CD107a, IFN-γ, and TNF-α are shown. Differences between the two groups were tested by using the nonparametric two-tailed Mann–Whitney test. (B) Responding T cells from Fig. 3_A_ were divided into three groups: degranulation (CD107a) only, degranulation and cytokine production, and cytokine production only. Pie charts show the percentages of the functional cells to total responding T cells from patients in the DF and DHF groups. The average percentages were calculated by summing the percentages from individuals and dividing by number of cases.
Fig. 4.
MHC tetramer analysis of the HLA-A11-restricted NS3-GTS response. (A) PBMC from 10 secondary dengue-infected patients, 5 DF and 5 DHF (
Table S3
), were stained with the HLA-A*11-NS3-GTS tetramer corresponding to the serotype of their secondary infection. After stimulation with the same peptide used for tetramer staining and in the presence of anti-CD107a Ab, cells were stained for CD8, TNF-α, and IFN-γ. (B) Pie charts showing the details of the tetramer-specific responses by following the format of Fig. 3_B_.
References
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