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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 analysis of HLA molecule restriction on CD8+ T-cell epitopes.The CD8+ T cell from donor 1 pre-sensitized with nonamer aa129–aa137 (A), donor 2 pre-sensitized with aa131–aa139 (B), donor 3 pre-sensitized with aa247–aa255 (C), and donor 4 pre-sensitized with aa167–aa175 (D) or aa277–aa285 (E) were tested against partially histocompatible EBV-B cells alone or pulsed with the particular peptide using in vitro IFN-γ ELISPOT assay. The HLA class I alleles shared between effectors and targets are indicated in ordinate. EBV-B, Epstein-barr virus-transformed B lymphoblast.
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pntd-0002076-g002: The analysis of HLA molecule restriction on CD8+ T-cell epitopes.The CD8+ T cell from donor 1 pre-sensitized with nonamer aa129–aa137 (A), donor 2 pre-sensitized with aa131–aa139 (B), donor 3 pre-sensitized with aa247–aa255 (C), and donor 4 pre-sensitized with aa167–aa175 (D) or aa277–aa285 (E) were tested against partially histocompatible EBV-B cells alone or pulsed with the particular peptide using in vitro IFN-γ ELISPOT assay. The HLA class I alleles shared between effectors and targets are indicated in ordinate. EBV-B, Epstein-barr virus-transformed B lymphoblast.

Mentions: The in vitro peptide-specific pre-sensitized CD8+ T cells were successfully generated from all four donors, as defined by a flow cytometry analysis (data not show). The HLA-matched and mismatched EBV-B cells used to confirm HLA restrictions and the HLA class I molecules of the patients were shown in Figure 2. The nonamers recognized by these CD8+ T cells in the four donors were restricted by three different HLA class I alleles (Table 1). These novel nonamer epitopes were further supported by the binding motifs, mainly anchor residues at position 2 or position 9. The epitope aa129–aa137 fits the HLA-A2 binding motif at the anchor residues position 2 (leucine, valine or glutarnine). Epitopes aa131–aa139 and aa247–aa255 fit the HLA-B35 binding motif, including anchor residues at position 2 (proline, alanine, or valine) and the C terminus (leucine, tyrosine, or methionine). Epitopes aa167–aa175 and aa277–aa285 fit the HLA-A33 binding motif, including anchor residues at position 2 (alanine, isoleucine or valine) and the C terminus (arginine) [29]. When comparing HTNV to other Hantaviruses, the sequences of the epitopes aa129–aa137, aa131–aa139, and aa167–aa175 were conserved well with 67%–100% concordance among Hantaviruses, whereas the epitopes aa247–aa255 and aa277–aa285 were less well conserved (Table 2).


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 analysis of HLA molecule restriction on CD8+ T-cell epitopes.The CD8+ T cell from donor 1 pre-sensitized with nonamer aa129–aa137 (A), donor 2 pre-sensitized with aa131–aa139 (B), donor 3 pre-sensitized with aa247–aa255 (C), and donor 4 pre-sensitized with aa167–aa175 (D) or aa277–aa285 (E) were tested against partially histocompatible EBV-B cells alone or pulsed with the particular peptide using in vitro IFN-γ ELISPOT assay. The HLA class I alleles shared between effectors and targets are indicated in ordinate. EBV-B, Epstein-barr virus-transformed B lymphoblast.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0002076-g002: The analysis of HLA molecule restriction on CD8+ T-cell epitopes.The CD8+ T cell from donor 1 pre-sensitized with nonamer aa129–aa137 (A), donor 2 pre-sensitized with aa131–aa139 (B), donor 3 pre-sensitized with aa247–aa255 (C), and donor 4 pre-sensitized with aa167–aa175 (D) or aa277–aa285 (E) were tested against partially histocompatible EBV-B cells alone or pulsed with the particular peptide using in vitro IFN-γ ELISPOT assay. The HLA class I alleles shared between effectors and targets are indicated in ordinate. EBV-B, Epstein-barr virus-transformed B lymphoblast.
Mentions: The in vitro peptide-specific pre-sensitized CD8+ T cells were successfully generated from all four donors, as defined by a flow cytometry analysis (data not show). The HLA-matched and mismatched EBV-B cells used to confirm HLA restrictions and the HLA class I molecules of the patients were shown in Figure 2. The nonamers recognized by these CD8+ T cells in the four donors were restricted by three different HLA class I alleles (Table 1). These novel nonamer epitopes were further supported by the binding motifs, mainly anchor residues at position 2 or position 9. The epitope aa129–aa137 fits the HLA-A2 binding motif at the anchor residues position 2 (leucine, valine or glutarnine). Epitopes aa131–aa139 and aa247–aa255 fit the HLA-B35 binding motif, including anchor residues at position 2 (proline, alanine, or valine) and the C terminus (leucine, tyrosine, or methionine). Epitopes aa167–aa175 and aa277–aa285 fit the HLA-A33 binding motif, including anchor residues at position 2 (alanine, isoleucine or valine) and the C terminus (arginine) [29]. When comparing HTNV to other Hantaviruses, the sequences of the epitopes aa129–aa137, aa131–aa139, and aa167–aa175 were conserved well with 67%–100% concordance among Hantaviruses, whereas the epitopes aa247–aa255 and aa277–aa285 were less well conserved (Table 2).

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