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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 accurate detection of HTNV nucleoprotein epitope-specific CD8+ T-cell response with HLA-peptide pentamer staining.(A) The PBMCs from HLA-A2+ donors P4 (mild) or P14 (severe) were stained with A2-pentamer preloaded of peptide aa129–aa137. (B) The PBMCs from HLA-B35+ donors P29 (moderate) or P32 (severe) were stained with B35-pentamer preloaded of aa131–aa139. Each of the donors has two time points, including febrile/oliguric and diuretic stages. A healthy person with HLA-A2 or B35 was stained as a normal control. The patient without HLA-A2 or B35 was used as an HLA allele control. The HLA-A2+ or B35+ patient stained with HLA-B35 or A2 pentamer, respectively, was used as a peptide control. HLA, human leukocyte antigen.
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pntd-0002076-g003: The accurate detection of HTNV nucleoprotein epitope-specific CD8+ T-cell response with HLA-peptide pentamer staining.(A) The PBMCs from HLA-A2+ donors P4 (mild) or P14 (severe) were stained with A2-pentamer preloaded of peptide aa129–aa137. (B) The PBMCs from HLA-B35+ donors P29 (moderate) or P32 (severe) were stained with B35-pentamer preloaded of aa131–aa139. Each of the donors has two time points, including febrile/oliguric and diuretic stages. A healthy person with HLA-A2 or B35 was stained as a normal control. The patient without HLA-A2 or B35 was used as an HLA allele control. The HLA-A2+ or B35+ patient stained with HLA-B35 or A2 pentamer, respectively, was used as a peptide control. HLA, human leukocyte antigen.

Mentions: Since HLA-A2 is the most frequent allele (29.7%) of HLA-A loci in the Chinese Han population and HLA-B35 is a major allele in HLA-B loci [30], we focused the epitopes aa129–aa137 and aa131–aa139 restricted by HLA-A2 and HLA-B35, respectively, and generated the HLA class I peptide pentameric complex for these two HTNV-NP epitopes. Twenty-five HLA-A2+ patients and eight HLA-B35+ patients with a different severity of HFRS were tested at early and late time points during hospitalization. Epitope aa129–aa137-specific pentamer+ CD8+ T cells in PBMCs could be detected in 11 of the 12 (91.7%) patients with mild/moderate severity as compared with 7 of the 13 (53.8%) performed on severe/critical patients (Table S1). (Fisher's exact chi-square test, P = 0.073). The frequency of CD8+ T cells that were specific for the HLA-A2-restricted epitope aa129–aa137 ranged from 0.010 to 0.700% (CI95%: 0.080%–0.208%). For the HLA-B35+ patients, the frequency of the circulating CD8+ T cells that were specific for the epitope aa131–aa139 ranged from 0.010 to 0.185% (CI95%: 0.030%–0.094%) (Figure 3).


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 accurate detection of HTNV nucleoprotein epitope-specific CD8+ T-cell response with HLA-peptide pentamer staining.(A) The PBMCs from HLA-A2+ donors P4 (mild) or P14 (severe) were stained with A2-pentamer preloaded of peptide aa129–aa137. (B) The PBMCs from HLA-B35+ donors P29 (moderate) or P32 (severe) were stained with B35-pentamer preloaded of aa131–aa139. Each of the donors has two time points, including febrile/oliguric and diuretic stages. A healthy person with HLA-A2 or B35 was stained as a normal control. The patient without HLA-A2 or B35 was used as an HLA allele control. The HLA-A2+ or B35+ patient stained with HLA-B35 or A2 pentamer, respectively, was used as a peptide control. HLA, human leukocyte antigen.
© Copyright Policy
Related In: Results  -  Collection

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

pntd-0002076-g003: The accurate detection of HTNV nucleoprotein epitope-specific CD8+ T-cell response with HLA-peptide pentamer staining.(A) The PBMCs from HLA-A2+ donors P4 (mild) or P14 (severe) were stained with A2-pentamer preloaded of peptide aa129–aa137. (B) The PBMCs from HLA-B35+ donors P29 (moderate) or P32 (severe) were stained with B35-pentamer preloaded of aa131–aa139. Each of the donors has two time points, including febrile/oliguric and diuretic stages. A healthy person with HLA-A2 or B35 was stained as a normal control. The patient without HLA-A2 or B35 was used as an HLA allele control. The HLA-A2+ or B35+ patient stained with HLA-B35 or A2 pentamer, respectively, was used as a peptide control. HLA, human leukocyte antigen.
Mentions: Since HLA-A2 is the most frequent allele (29.7%) of HLA-A loci in the Chinese Han population and HLA-B35 is a major allele in HLA-B loci [30], we focused the epitopes aa129–aa137 and aa131–aa139 restricted by HLA-A2 and HLA-B35, respectively, and generated the HLA class I peptide pentameric complex for these two HTNV-NP epitopes. Twenty-five HLA-A2+ patients and eight HLA-B35+ patients with a different severity of HFRS were tested at early and late time points during hospitalization. Epitope aa129–aa137-specific pentamer+ CD8+ T cells in PBMCs could be detected in 11 of the 12 (91.7%) patients with mild/moderate severity as compared with 7 of the 13 (53.8%) performed on severe/critical patients (Table S1). (Fisher's exact chi-square test, P = 0.073). The frequency of CD8+ T cells that were specific for the HLA-A2-restricted epitope aa129–aa137 ranged from 0.010 to 0.700% (CI95%: 0.080%–0.208%). For the HLA-B35+ patients, the frequency of the circulating CD8+ T cells that were specific for the epitope aa131–aa139 ranged from 0.010 to 0.185% (CI95%: 0.030%–0.094%) (Figure 3).

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