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Hantaan virus infection induces both Th1 and ThGranzyme B+ cell immune responses that associated with viral control and clinical outcome in humans.

Ma Y, Yuan B, Zhuang R, Zhang Y, Liu B, Zhang C, Zhang Y, Yu H, Yi J, Yang A, Jin B - PLoS Pathog. (2015)

Bottom Line: Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4(+)T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome.Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4(+)T-cell responses against HTNV glycoproteins compared with more severe patients.The host defense mediated by CD4(+)T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells.

View Article: PubMed Central - PubMed

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

ABSTRACT
Hantaviruses infection causing severe emerging diseases with high mortality rates in humans has become public health concern globally. The potential roles of CD4(+)T cells in viral control have been extensively studied. However, the contribution of CD4(+)T cells to the host response against Hantaan virus (HTNV) infection remains unclear. Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4(+)T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome. A total of 79 novel 15-mer T-cell epitopes on the HTNV glycoprotein were identified, among which 20 peptides were dominant target epitopes. Importantly, we showed the presence of both effective Th1 responses with polyfunctional cytokine secretion and ThGranzyme B(+) cell responses with cytotoxic mediators production against HTNV infection. The HTNV glycoprotein-specific CD4(+)T-cell responses inversely correlated with the plasma HTNV RNA load in patients. Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4(+)T-cell responses against HTNV glycoproteins compared with more severe patients. The CD4(+)T cells characterized by broader antigenic repertoire, stronger polyfunctional responses, better expansion capacity and highly differentiated effector memory phenotype(CD27-CD28-CCR7-CD45RA-CD127(hi)) would elicit greater defense against HTNV infection and lead to much milder outcome of the disease. The host defense mediated by CD4(+)T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells. Thus, these findings highlight the efforts of CD4(+)T-cell immunity to HTNV control and provide crucial information to better understand the immune defense against HTNV infection.

No MeSH data available.


Related in: MedlinePlus

Analysis of the active, memory or differentiation phenotypes of HTNV-Gn/Gc-specific CD4+T cells in HFRS patients.(A) Representative histogram of CD38 expression on HTNV-Gn/Gc-specific CD4+T cells during different stages of the disease. FACS contour plots were gated on CD3+CD4+T cells. (B) Comparison of the memory phenotype constitution percentage of naïve (CCR7+CD45RA+), effector memory (CCR7–CD45RA–), central memory (CCR7+CD45RA–) and transitional effector memory (CCR7–CD45RA+) CD4+T-cell subsets in mild/moderate patients and severe/critical patients during acute HFRS. (C) The memory phenotype constitution percentage in IFN-γ or granzyme B-producing CD4+T cells. (D) Comparison of the differentiation phenotype percentage of early (CD27+CD28+), intermediate (CD27–CD28+) and full differentiation (CD27–CD28–) CD4+T-cell subsets in mild/moderate patients and severe/critical patients at acute stage of HFRS. (E) Comparison of the PD-1, CD57 and CD127 expression on CD4+T cells in mild/moderate and severe/critical patients during acute phase of HFRS. The Wilcoxon rank sum test was used for statistical evaluation; *P<0.05, **P<0.01, *** P<0.001, ns, not significant. MFI, mean fluorescence intensity; Gran B, granzyme B.
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ppat.1004788.g008: Analysis of the active, memory or differentiation phenotypes of HTNV-Gn/Gc-specific CD4+T cells in HFRS patients.(A) Representative histogram of CD38 expression on HTNV-Gn/Gc-specific CD4+T cells during different stages of the disease. FACS contour plots were gated on CD3+CD4+T cells. (B) Comparison of the memory phenotype constitution percentage of naïve (CCR7+CD45RA+), effector memory (CCR7–CD45RA–), central memory (CCR7+CD45RA–) and transitional effector memory (CCR7–CD45RA+) CD4+T-cell subsets in mild/moderate patients and severe/critical patients during acute HFRS. (C) The memory phenotype constitution percentage in IFN-γ or granzyme B-producing CD4+T cells. (D) Comparison of the differentiation phenotype percentage of early (CD27+CD28+), intermediate (CD27–CD28+) and full differentiation (CD27–CD28–) CD4+T-cell subsets in mild/moderate patients and severe/critical patients at acute stage of HFRS. (E) Comparison of the PD-1, CD57 and CD127 expression on CD4+T cells in mild/moderate and severe/critical patients during acute phase of HFRS. The Wilcoxon rank sum test was used for statistical evaluation; *P<0.05, **P<0.01, *** P<0.001, ns, not significant. MFI, mean fluorescence intensity; Gran B, granzyme B.

Mentions: To characterize the overall phenotype of HTNV-Gn/Gc-specific CD4+T cells, we first defined the activation extent of CD4+T cells. After stimulation with HTNV-Gn/Gc-overlapping peptide pools, the CD38 expression in circulating blood CD4+T cells was upregulated, peaking at the febrile stage of HFRS (MFI 182) (Fig 8A). The maximal activity of HTNV-Gn/Gc-specific CD4+T cells at the febrile stage might reflect a rapid and prominent CD4+T-cell response against HTNV infection after disease onset, prompting further examination of the phenotype characteristics of efficient CD4+T cells.


Hantaan virus infection induces both Th1 and ThGranzyme B+ cell immune responses that associated with viral control and clinical outcome in humans.

Ma Y, Yuan B, Zhuang R, Zhang Y, Liu B, Zhang C, Zhang Y, Yu H, Yi J, Yang A, Jin B - PLoS Pathog. (2015)

Analysis of the active, memory or differentiation phenotypes of HTNV-Gn/Gc-specific CD4+T cells in HFRS patients.(A) Representative histogram of CD38 expression on HTNV-Gn/Gc-specific CD4+T cells during different stages of the disease. FACS contour plots were gated on CD3+CD4+T cells. (B) Comparison of the memory phenotype constitution percentage of naïve (CCR7+CD45RA+), effector memory (CCR7–CD45RA–), central memory (CCR7+CD45RA–) and transitional effector memory (CCR7–CD45RA+) CD4+T-cell subsets in mild/moderate patients and severe/critical patients during acute HFRS. (C) The memory phenotype constitution percentage in IFN-γ or granzyme B-producing CD4+T cells. (D) Comparison of the differentiation phenotype percentage of early (CD27+CD28+), intermediate (CD27–CD28+) and full differentiation (CD27–CD28–) CD4+T-cell subsets in mild/moderate patients and severe/critical patients at acute stage of HFRS. (E) Comparison of the PD-1, CD57 and CD127 expression on CD4+T cells in mild/moderate and severe/critical patients during acute phase of HFRS. The Wilcoxon rank sum test was used for statistical evaluation; *P<0.05, **P<0.01, *** P<0.001, ns, not significant. MFI, mean fluorescence intensity; Gran B, granzyme B.
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Related In: Results  -  Collection

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ppat.1004788.g008: Analysis of the active, memory or differentiation phenotypes of HTNV-Gn/Gc-specific CD4+T cells in HFRS patients.(A) Representative histogram of CD38 expression on HTNV-Gn/Gc-specific CD4+T cells during different stages of the disease. FACS contour plots were gated on CD3+CD4+T cells. (B) Comparison of the memory phenotype constitution percentage of naïve (CCR7+CD45RA+), effector memory (CCR7–CD45RA–), central memory (CCR7+CD45RA–) and transitional effector memory (CCR7–CD45RA+) CD4+T-cell subsets in mild/moderate patients and severe/critical patients during acute HFRS. (C) The memory phenotype constitution percentage in IFN-γ or granzyme B-producing CD4+T cells. (D) Comparison of the differentiation phenotype percentage of early (CD27+CD28+), intermediate (CD27–CD28+) and full differentiation (CD27–CD28–) CD4+T-cell subsets in mild/moderate patients and severe/critical patients at acute stage of HFRS. (E) Comparison of the PD-1, CD57 and CD127 expression on CD4+T cells in mild/moderate and severe/critical patients during acute phase of HFRS. The Wilcoxon rank sum test was used for statistical evaluation; *P<0.05, **P<0.01, *** P<0.001, ns, not significant. MFI, mean fluorescence intensity; Gran B, granzyme B.
Mentions: To characterize the overall phenotype of HTNV-Gn/Gc-specific CD4+T cells, we first defined the activation extent of CD4+T cells. After stimulation with HTNV-Gn/Gc-overlapping peptide pools, the CD38 expression in circulating blood CD4+T cells was upregulated, peaking at the febrile stage of HFRS (MFI 182) (Fig 8A). The maximal activity of HTNV-Gn/Gc-specific CD4+T cells at the febrile stage might reflect a rapid and prominent CD4+T-cell response against HTNV infection after disease onset, prompting further examination of the phenotype characteristics of efficient CD4+T cells.

Bottom Line: Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4(+)T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome.Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4(+)T-cell responses against HTNV glycoproteins compared with more severe patients.The host defense mediated by CD4(+)T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells.

View Article: PubMed Central - PubMed

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

ABSTRACT
Hantaviruses infection causing severe emerging diseases with high mortality rates in humans has become public health concern globally. The potential roles of CD4(+)T cells in viral control have been extensively studied. However, the contribution of CD4(+)T cells to the host response against Hantaan virus (HTNV) infection remains unclear. Here, based on the T-cell epitopes mapped on HTNV glycoprotein, we studied the effects and characteristics of CD4(+)T-cell responses in determining the outcome of hemorrhagic fever with renal syndrome. A total of 79 novel 15-mer T-cell epitopes on the HTNV glycoprotein were identified, among which 20 peptides were dominant target epitopes. Importantly, we showed the presence of both effective Th1 responses with polyfunctional cytokine secretion and ThGranzyme B(+) cell responses with cytotoxic mediators production against HTNV infection. The HTNV glycoprotein-specific CD4(+)T-cell responses inversely correlated with the plasma HTNV RNA load in patients. Individuals with milder disease outcomes showed broader epitopes targeted and stronger CD4(+)T-cell responses against HTNV glycoproteins compared with more severe patients. The CD4(+)T cells characterized by broader antigenic repertoire, stronger polyfunctional responses, better expansion capacity and highly differentiated effector memory phenotype(CD27-CD28-CCR7-CD45RA-CD127(hi)) would elicit greater defense against HTNV infection and lead to much milder outcome of the disease. The host defense mediated by CD4(+)T cells may through the inducing antiviral condition of the host cells and cytotoxic effect of ThGranzyme B+ cells. Thus, these findings highlight the efforts of CD4(+)T-cell immunity to HTNV control and provide crucial information to better understand the immune defense against HTNV infection.

No MeSH data available.


Related in: MedlinePlus