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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

The expansion capacity of HTNV-Gn/Gc-specific CD4+T cells is associated with viremia control in HFRS patients.(A) Representative flow cytometric plots of the expansion percentage of CD4+ or CD8+T cells stimulated by the HTNV-Gn/Gc or polyclonal activator SEB control during acute HFRS. The expansion extent of the HTNV-Gn/Gc-specific CD4+ or CD8+T cells is shown in the upper left quadrants of each figure, reflecting the decrease of CFSE in the dividing CD4+ or CD8+T cells. The numbers denote the percentage of cells within the boxed regions. The overlay of the three conditions in histograms clearly demonstrate that the CFSE curve of both CD4+ and CD8+T cells from the SEB stimulation is shifted more to the right than that stimulated by the HTNV-Gn/Gc. The upper and the lower lanes show the expansion capacities of the representative mild/moderate and severe/critical patient, respectively. (B-C) Comparison of the percentage (B) and MFI (C) of CFSEdim CD4+T cells stimulated by HTNV-Gn/Gc at the acute phase of HFRS between mild/moderate and severe/critical patients. (D) Analysis of the correlation between the percentage and the MFI of CFSEdim CD4+T cells. (E) Analysis of the correlations between the percentage of CFSEdim CD4+T cells and the plasma HTNV RNA load of HFRS. (F-G) The correlation of the MFI (F) or percentage (G) between CFSEdim CD4+T cells and CFSEdim CD8+T cells stimulated by HTNV-Gn/Gc during acute HFRS. Each spot represents a single patient. The Wilcoxon rank sum test and Spearman’s rank test were used for statistical evaluation. SEB, staphylococcal enterotoxin B; MFI, mean fluorescence intensity; CFSE, carboxyfluorescein succinimidyl ester.
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ppat.1004788.g007: The expansion capacity of HTNV-Gn/Gc-specific CD4+T cells is associated with viremia control in HFRS patients.(A) Representative flow cytometric plots of the expansion percentage of CD4+ or CD8+T cells stimulated by the HTNV-Gn/Gc or polyclonal activator SEB control during acute HFRS. The expansion extent of the HTNV-Gn/Gc-specific CD4+ or CD8+T cells is shown in the upper left quadrants of each figure, reflecting the decrease of CFSE in the dividing CD4+ or CD8+T cells. The numbers denote the percentage of cells within the boxed regions. The overlay of the three conditions in histograms clearly demonstrate that the CFSE curve of both CD4+ and CD8+T cells from the SEB stimulation is shifted more to the right than that stimulated by the HTNV-Gn/Gc. The upper and the lower lanes show the expansion capacities of the representative mild/moderate and severe/critical patient, respectively. (B-C) Comparison of the percentage (B) and MFI (C) of CFSEdim CD4+T cells stimulated by HTNV-Gn/Gc at the acute phase of HFRS between mild/moderate and severe/critical patients. (D) Analysis of the correlation between the percentage and the MFI of CFSEdim CD4+T cells. (E) Analysis of the correlations between the percentage of CFSEdim CD4+T cells and the plasma HTNV RNA load of HFRS. (F-G) The correlation of the MFI (F) or percentage (G) between CFSEdim CD4+T cells and CFSEdim CD8+T cells stimulated by HTNV-Gn/Gc during acute HFRS. Each spot represents a single patient. The Wilcoxon rank sum test and Spearman’s rank test were used for statistical evaluation. SEB, staphylococcal enterotoxin B; MFI, mean fluorescence intensity; CFSE, carboxyfluorescein succinimidyl ester.

Mentions: We next assessed whether the antivirus effect of CD4+T cells was dependent on the capacity of expansion. The CFSE staining assay showed that HTNV-Gn/Gc-specific CD4+T-cell expansion was readily detectable in HFRS individuals at the acute phase of the disease (representative in Fig 7A and others in S8 and S9 Figs). However, a significant difference in the CD4+T-cell expansion to HTNV-Gn/Gc between two different groups was observed. The percentage of CFSEdim CD4+T cells in mild/moderate patients was higher than that in severe/critical patients (Fig 7B, P = 0.0013), and the mean fluorescence intensity (MFI) of CFSEdim CD4+T cells was lower in milder patients than that in more severe HFRS individuals (Fig 7C, P = 0.0345). Meanwhile, the MFI of CFSEdim CD4+T cells was inversely associated with the percentage of CFSEdim CD4+T cells at acute phase of HFRS (Fig 7D, P = 0.0199, r = −0.5158). These data indicated that milder disease severity was associated with more vigorous HTNV-Gn/Gc-specific CD4+T-cell expansion, whereas an impaired expansion capacity of HTNV-Gn/Gc-specific CD4+T cells was shown in severe/critical patients. However, when stimulated with the polyclonal activator SBE as control, both CD4+ and CD8+ T cells of the HFRS patients presented proliferative activity with a large proportion of CFSEdim cells (representative in Fig 7A and others in S9 Fig), which was obviously higher than that stimulated with HTNV-Gn/Gc peptides (S10 Fig, P = 0.0049 for CD4+T cell and P = 0.0005 for CD8+T cell), suggesting that the impaired T-cell expansion in severe/critical HFRS patients may be refractory to the specific HTNV-Gn/Gc stimulation, but not susceptible to a systemic cell death after activation.


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)

The expansion capacity of HTNV-Gn/Gc-specific CD4+T cells is associated with viremia control in HFRS patients.(A) Representative flow cytometric plots of the expansion percentage of CD4+ or CD8+T cells stimulated by the HTNV-Gn/Gc or polyclonal activator SEB control during acute HFRS. The expansion extent of the HTNV-Gn/Gc-specific CD4+ or CD8+T cells is shown in the upper left quadrants of each figure, reflecting the decrease of CFSE in the dividing CD4+ or CD8+T cells. The numbers denote the percentage of cells within the boxed regions. The overlay of the three conditions in histograms clearly demonstrate that the CFSE curve of both CD4+ and CD8+T cells from the SEB stimulation is shifted more to the right than that stimulated by the HTNV-Gn/Gc. The upper and the lower lanes show the expansion capacities of the representative mild/moderate and severe/critical patient, respectively. (B-C) Comparison of the percentage (B) and MFI (C) of CFSEdim CD4+T cells stimulated by HTNV-Gn/Gc at the acute phase of HFRS between mild/moderate and severe/critical patients. (D) Analysis of the correlation between the percentage and the MFI of CFSEdim CD4+T cells. (E) Analysis of the correlations between the percentage of CFSEdim CD4+T cells and the plasma HTNV RNA load of HFRS. (F-G) The correlation of the MFI (F) or percentage (G) between CFSEdim CD4+T cells and CFSEdim CD8+T cells stimulated by HTNV-Gn/Gc during acute HFRS. Each spot represents a single patient. The Wilcoxon rank sum test and Spearman’s rank test were used for statistical evaluation. SEB, staphylococcal enterotoxin B; MFI, mean fluorescence intensity; CFSE, carboxyfluorescein succinimidyl ester.
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Related In: Results  -  Collection

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ppat.1004788.g007: The expansion capacity of HTNV-Gn/Gc-specific CD4+T cells is associated with viremia control in HFRS patients.(A) Representative flow cytometric plots of the expansion percentage of CD4+ or CD8+T cells stimulated by the HTNV-Gn/Gc or polyclonal activator SEB control during acute HFRS. The expansion extent of the HTNV-Gn/Gc-specific CD4+ or CD8+T cells is shown in the upper left quadrants of each figure, reflecting the decrease of CFSE in the dividing CD4+ or CD8+T cells. The numbers denote the percentage of cells within the boxed regions. The overlay of the three conditions in histograms clearly demonstrate that the CFSE curve of both CD4+ and CD8+T cells from the SEB stimulation is shifted more to the right than that stimulated by the HTNV-Gn/Gc. The upper and the lower lanes show the expansion capacities of the representative mild/moderate and severe/critical patient, respectively. (B-C) Comparison of the percentage (B) and MFI (C) of CFSEdim CD4+T cells stimulated by HTNV-Gn/Gc at the acute phase of HFRS between mild/moderate and severe/critical patients. (D) Analysis of the correlation between the percentage and the MFI of CFSEdim CD4+T cells. (E) Analysis of the correlations between the percentage of CFSEdim CD4+T cells and the plasma HTNV RNA load of HFRS. (F-G) The correlation of the MFI (F) or percentage (G) between CFSEdim CD4+T cells and CFSEdim CD8+T cells stimulated by HTNV-Gn/Gc during acute HFRS. Each spot represents a single patient. The Wilcoxon rank sum test and Spearman’s rank test were used for statistical evaluation. SEB, staphylococcal enterotoxin B; MFI, mean fluorescence intensity; CFSE, carboxyfluorescein succinimidyl ester.
Mentions: We next assessed whether the antivirus effect of CD4+T cells was dependent on the capacity of expansion. The CFSE staining assay showed that HTNV-Gn/Gc-specific CD4+T-cell expansion was readily detectable in HFRS individuals at the acute phase of the disease (representative in Fig 7A and others in S8 and S9 Figs). However, a significant difference in the CD4+T-cell expansion to HTNV-Gn/Gc between two different groups was observed. The percentage of CFSEdim CD4+T cells in mild/moderate patients was higher than that in severe/critical patients (Fig 7B, P = 0.0013), and the mean fluorescence intensity (MFI) of CFSEdim CD4+T cells was lower in milder patients than that in more severe HFRS individuals (Fig 7C, P = 0.0345). Meanwhile, the MFI of CFSEdim CD4+T cells was inversely associated with the percentage of CFSEdim CD4+T cells at acute phase of HFRS (Fig 7D, P = 0.0199, r = −0.5158). These data indicated that milder disease severity was associated with more vigorous HTNV-Gn/Gc-specific CD4+T-cell expansion, whereas an impaired expansion capacity of HTNV-Gn/Gc-specific CD4+T cells was shown in severe/critical patients. However, when stimulated with the polyclonal activator SBE as control, both CD4+ and CD8+ T cells of the HFRS patients presented proliferative activity with a large proportion of CFSEdim cells (representative in Fig 7A and others in S9 Fig), which was obviously higher than that stimulated with HTNV-Gn/Gc peptides (S10 Fig, P = 0.0049 for CD4+T cell and P = 0.0005 for CD8+T cell), suggesting that the impaired T-cell expansion in severe/critical HFRS patients may be refractory to the specific HTNV-Gn/Gc stimulation, but not susceptible to a systemic cell death after activation.

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