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HLA-A2 and B35 restricted hantaan virus nucleoprotein CD8+ T-cell epitope-specific immune response correlates with milder disease in hemorrhagic fever with renal syndrome.

Ma Y, Wang J, Yuan B, Wang M, Zhang Y, Xu Z, Zhang C, Zhang Y, Liu B, Yi J, Yang K, Yang A, Zhuang R, Jin B - PLoS Negl Trop Dis (2013)

Bottom Line: Moreover, the frequency of epitope-specific CD8(+) T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization.The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8(+) T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation.The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8(+) T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, the Fourth Military Medical University, Xi'an, China.

ABSTRACT

Background: Hantaan virus (HTNV) infection in humans is a serious public health concern in Asia. A potent T cell activation peptide vaccine from HTNV structure protein represents a promising immunotherapy for disease control. However, the T cell epitopes of the HTNV restricted by the HLA alleles and the role of epitope-specific T cell response after HTNV infection remain largely unexplored.

Methodology/principal findings: Five well-conserved novel CD8(+) T-cell epitopes of the HTNV nucleoprotein restricted by the most popular HLA alleles in Chinese Han population were defined with interferon-γ enzyme-linked immunospot assay in 37 patients infected with HTNV during hospitalization. Two epitopes aa129-aa137 and aa131-aa139 restricted by HLA-A2 and B35, respectively, were selected to evaluate the epitope-specific CD8(+) T-cell response. HLA-peptide pentamer complex staining showed that the frequency of single epitope-specific CD8(+) T cell could be detected in patients (95% confidence interval for aa129-aa137: 0.080%-0.208%; for aa131-aa139: 0.030%-0.094%). The frequency of epitope-specific pentamer(+) CD8(+) T-cell response was much higher in mild/moderate patients than in severe/critical ones at the acute stage of the disease. Moreover, the frequency of epitope-specific CD8(+) T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization. The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8(+) T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation.

Conclusion/significance: The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8(+) T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans.

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Related in: MedlinePlus

The proliferation capacity of HTNV nucleoprotein epitope-specific CD8+ T cells at acute stage of HFRS.(A) The PBMCs of four HLA-A2+ patients with different severities stimulated with the epitope aa129–aa137 were detected. FACS contour plots were gated on CD3+ CD8+ cells. The proliferative potential of the epitope-specific CD8+ pentamer+ T cells was shown in the upper left quadrants in the upper lane of the figure suggesting the loss of CFSE in the dividing CD8+ T cells. The lower lane showed the proliferative capacity of the two CD8+ T-cell subsets. (B) The comparison of the frequency of HLA-A2-pentamer+ CFSElow proliferating CD8+ T cells between mild/moderate patients and severe/critical patients at acute stage of the disease (Mann-Whitney U test). P values of ≤0.05 were considered statistically significant. CFSE, 5, 6-carboxyf luorescein succinimidyl ester. SEB, Staphylococcal enterotoxin B.
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pntd-0002076-g006: The proliferation capacity of HTNV nucleoprotein epitope-specific CD8+ T cells at acute stage of HFRS.(A) The PBMCs of four HLA-A2+ patients with different severities stimulated with the epitope aa129–aa137 were detected. FACS contour plots were gated on CD3+ CD8+ cells. The proliferative potential of the epitope-specific CD8+ pentamer+ T cells was shown in the upper left quadrants in the upper lane of the figure suggesting the loss of CFSE in the dividing CD8+ T cells. The lower lane showed the proliferative capacity of the two CD8+ T-cell subsets. (B) The comparison of the frequency of HLA-A2-pentamer+ CFSElow proliferating CD8+ T cells between mild/moderate patients and severe/critical patients at acute stage of the disease (Mann-Whitney U test). P values of ≤0.05 were considered statistically significant. CFSE, 5, 6-carboxyf luorescein succinimidyl ester. SEB, Staphylococcal enterotoxin B.

Mentions: Interestingly, it seemed that there were two subsets of CD8+ T cells in PBMCs with high or low mean fluorescence intensity, both of which could respond to the specific epitopes presented by the pentamers (Figure 3). The further staining showed that both CD8hi and CD8lo T cells were CD8αβ heterodimer expression (Figure S1). The much higher ratio of CD8lo/CD8hi T cell-numbers in the acute stage would decline at late stage of HFRS. Both the CD8lo and CD8hi T cell subsets could produce IFN-γ when stimulated with specific epitopes (Figure 5A). However, a stronger proliferative capacity of epitope-specific CD8hi T cell subset than that in the CD8lo T cell subset at the acute stage was observed, as shown by the pentamer+ cells in the upper left quadrants of the dot plots (Figure 6Alower panel).


HLA-A2 and B35 restricted hantaan virus nucleoprotein CD8+ T-cell epitope-specific immune response correlates with milder disease in hemorrhagic fever with renal syndrome.

Ma Y, Wang J, Yuan B, Wang M, Zhang Y, Xu Z, Zhang C, Zhang Y, Liu B, Yi J, Yang K, Yang A, Zhuang R, Jin B - PLoS Negl Trop Dis (2013)

The proliferation capacity of HTNV nucleoprotein epitope-specific CD8+ T cells at acute stage of HFRS.(A) The PBMCs of four HLA-A2+ patients with different severities stimulated with the epitope aa129–aa137 were detected. FACS contour plots were gated on CD3+ CD8+ cells. The proliferative potential of the epitope-specific CD8+ pentamer+ T cells was shown in the upper left quadrants in the upper lane of the figure suggesting the loss of CFSE in the dividing CD8+ T cells. The lower lane showed the proliferative capacity of the two CD8+ T-cell subsets. (B) The comparison of the frequency of HLA-A2-pentamer+ CFSElow proliferating CD8+ T cells between mild/moderate patients and severe/critical patients at acute stage of the disease (Mann-Whitney U test). P values of ≤0.05 were considered statistically significant. CFSE, 5, 6-carboxyf luorescein succinimidyl ester. SEB, Staphylococcal enterotoxin B.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585118&req=5

pntd-0002076-g006: The proliferation capacity of HTNV nucleoprotein epitope-specific CD8+ T cells at acute stage of HFRS.(A) The PBMCs of four HLA-A2+ patients with different severities stimulated with the epitope aa129–aa137 were detected. FACS contour plots were gated on CD3+ CD8+ cells. The proliferative potential of the epitope-specific CD8+ pentamer+ T cells was shown in the upper left quadrants in the upper lane of the figure suggesting the loss of CFSE in the dividing CD8+ T cells. The lower lane showed the proliferative capacity of the two CD8+ T-cell subsets. (B) The comparison of the frequency of HLA-A2-pentamer+ CFSElow proliferating CD8+ T cells between mild/moderate patients and severe/critical patients at acute stage of the disease (Mann-Whitney U test). P values of ≤0.05 were considered statistically significant. CFSE, 5, 6-carboxyf luorescein succinimidyl ester. SEB, Staphylococcal enterotoxin B.
Mentions: Interestingly, it seemed that there were two subsets of CD8+ T cells in PBMCs with high or low mean fluorescence intensity, both of which could respond to the specific epitopes presented by the pentamers (Figure 3). The further staining showed that both CD8hi and CD8lo T cells were CD8αβ heterodimer expression (Figure S1). The much higher ratio of CD8lo/CD8hi T cell-numbers in the acute stage would decline at late stage of HFRS. Both the CD8lo and CD8hi T cell subsets could produce IFN-γ when stimulated with specific epitopes (Figure 5A). However, a stronger proliferative capacity of epitope-specific CD8hi T cell subset than that in the CD8lo T cell subset at the acute stage was observed, as shown by the pentamer+ cells in the upper left quadrants of the dot plots (Figure 6Alower panel).

Bottom Line: Moreover, the frequency of epitope-specific CD8(+) T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization.The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8(+) T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation.The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8(+) T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, the Fourth Military Medical University, Xi'an, China.

ABSTRACT

Background: Hantaan virus (HTNV) infection in humans is a serious public health concern in Asia. A potent T cell activation peptide vaccine from HTNV structure protein represents a promising immunotherapy for disease control. However, the T cell epitopes of the HTNV restricted by the HLA alleles and the role of epitope-specific T cell response after HTNV infection remain largely unexplored.

Methodology/principal findings: Five well-conserved novel CD8(+) T-cell epitopes of the HTNV nucleoprotein restricted by the most popular HLA alleles in Chinese Han population were defined with interferon-γ enzyme-linked immunospot assay in 37 patients infected with HTNV during hospitalization. Two epitopes aa129-aa137 and aa131-aa139 restricted by HLA-A2 and B35, respectively, were selected to evaluate the epitope-specific CD8(+) T-cell response. HLA-peptide pentamer complex staining showed that the frequency of single epitope-specific CD8(+) T cell could be detected in patients (95% confidence interval for aa129-aa137: 0.080%-0.208%; for aa131-aa139: 0.030%-0.094%). The frequency of epitope-specific pentamer(+) CD8(+) T-cell response was much higher in mild/moderate patients than in severe/critical ones at the acute stage of the disease. Moreover, the frequency of epitope-specific CD8(+) T cells at acute stage was inversely associated with the peak level of serum creatinine and was positively associated with the nadir platelet counts during the hospitalization. The intracellular cytokine staining and the proliferation assay showed that the effective epitope-specific CD8(+) T cells were characterized with the production of interferon-γ, expression of CD69 and the strong capacity of proliferation.

Conclusion/significance: The novel HLA class I restricted HTNV nucleoprotein epitopes-specific CD8(+) T-cell responses would be closely related with the progression and the severity of the disease, which could provide the first step toward effective peptide vaccine development against HTNV infection in humans.

Show MeSH
Related in: MedlinePlus