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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 correlations of HTNV-Gn/Gc-specific CD4+T-cell responses with CD8+T-cell immunity, viremia and clinical parameters.(A) Analysis ofthe correlations between the frequency of CD4+IL-2+T cells, CD4+IFN-γ+T cells, CD4+TNF-α+T cells, or CD4+granzyme B+T cells (x axis) and the percentage of CD8+IFN-γ+T cells (y axis) during the acute stage of HFRS. (B-D) Analysis of the relationship between the percentage of IFN-γ or granzyme B-producing CD4+T cells and the plasma HTNV RNA load (B), the serum creatinine levels (C), or platelets numbers (D) during acute HFRS. Each spot represents a single patient. (E) Longitudinal assessment of the HTNV RNA load, serum creatinine and the frequency of HTNV-Gn/Gc-specific IFN-+CD4+T cells in representative patients with moderate severity and representative patients with critical severity during the course of the disease. The line indicates the level of IFN-+CD4+T cells, white bars indicate the serum creatinine levels, and the shaded areas show the plasma HTNV RNA load of the patients tested. The Spearman’s rank test was used for statistical evaluation. Gran B, granzyme B.
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ppat.1004788.g005: The correlations of HTNV-Gn/Gc-specific CD4+T-cell responses with CD8+T-cell immunity, viremia and clinical parameters.(A) Analysis ofthe correlations between the frequency of CD4+IL-2+T cells, CD4+IFN-γ+T cells, CD4+TNF-α+T cells, or CD4+granzyme B+T cells (x axis) and the percentage of CD8+IFN-γ+T cells (y axis) during the acute stage of HFRS. (B-D) Analysis of the relationship between the percentage of IFN-γ or granzyme B-producing CD4+T cells and the plasma HTNV RNA load (B), the serum creatinine levels (C), or platelets numbers (D) during acute HFRS. Each spot represents a single patient. (E) Longitudinal assessment of the HTNV RNA load, serum creatinine and the frequency of HTNV-Gn/Gc-specific IFN-+CD4+T cells in representative patients with moderate severity and representative patients with critical severity during the course of the disease. The line indicates the level of IFN-+CD4+T cells, white bars indicate the serum creatinine levels, and the shaded areas show the plasma HTNV RNA load of the patients tested. The Spearman’s rank test was used for statistical evaluation. Gran B, granzyme B.

Mentions: Next, we measured the relationships between the frequencies of IFN-γ+CTLs and each Th1 cytokine-secreting CD4+T-cell subset. As expected, the frequencies of IL-2+CD4+, IFN-γ+CD4+ or TNF-α+CD4+T-cell subsets were positively correlated with the frequency of IFN-γ+CTLs (P = 0.018, r = 0.523 for IL-2+CD4+T cells; P = 0.001, r = 0.673 for IFN-γ+CD4+T cells; P = 0.007, r = 0.581 for TNF-α+CD4+T cells) (Fig 5A). In addition, the frequency of the granzyme B+CD4+T cells was also positively associated with the frequency of IFN-γ+CTLs (P = 0.041, r = 0.460) (Fig 5A), suggesting that ThGzmB+ cells are potential cytolytic effector cell subsets against HTNV infection.


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 correlations of HTNV-Gn/Gc-specific CD4+T-cell responses with CD8+T-cell immunity, viremia and clinical parameters.(A) Analysis ofthe correlations between the frequency of CD4+IL-2+T cells, CD4+IFN-γ+T cells, CD4+TNF-α+T cells, or CD4+granzyme B+T cells (x axis) and the percentage of CD8+IFN-γ+T cells (y axis) during the acute stage of HFRS. (B-D) Analysis of the relationship between the percentage of IFN-γ or granzyme B-producing CD4+T cells and the plasma HTNV RNA load (B), the serum creatinine levels (C), or platelets numbers (D) during acute HFRS. Each spot represents a single patient. (E) Longitudinal assessment of the HTNV RNA load, serum creatinine and the frequency of HTNV-Gn/Gc-specific IFN-+CD4+T cells in representative patients with moderate severity and representative patients with critical severity during the course of the disease. The line indicates the level of IFN-+CD4+T cells, white bars indicate the serum creatinine levels, and the shaded areas show the plasma HTNV RNA load of the patients tested. The Spearman’s rank test was used for statistical evaluation. Gran B, granzyme B.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4383613&req=5

ppat.1004788.g005: The correlations of HTNV-Gn/Gc-specific CD4+T-cell responses with CD8+T-cell immunity, viremia and clinical parameters.(A) Analysis ofthe correlations between the frequency of CD4+IL-2+T cells, CD4+IFN-γ+T cells, CD4+TNF-α+T cells, or CD4+granzyme B+T cells (x axis) and the percentage of CD8+IFN-γ+T cells (y axis) during the acute stage of HFRS. (B-D) Analysis of the relationship between the percentage of IFN-γ or granzyme B-producing CD4+T cells and the plasma HTNV RNA load (B), the serum creatinine levels (C), or platelets numbers (D) during acute HFRS. Each spot represents a single patient. (E) Longitudinal assessment of the HTNV RNA load, serum creatinine and the frequency of HTNV-Gn/Gc-specific IFN-+CD4+T cells in representative patients with moderate severity and representative patients with critical severity during the course of the disease. The line indicates the level of IFN-+CD4+T cells, white bars indicate the serum creatinine levels, and the shaded areas show the plasma HTNV RNA load of the patients tested. The Spearman’s rank test was used for statistical evaluation. Gran B, granzyme B.
Mentions: Next, we measured the relationships between the frequencies of IFN-γ+CTLs and each Th1 cytokine-secreting CD4+T-cell subset. As expected, the frequencies of IL-2+CD4+, IFN-γ+CD4+ or TNF-α+CD4+T-cell subsets were positively correlated with the frequency of IFN-γ+CTLs (P = 0.018, r = 0.523 for IL-2+CD4+T cells; P = 0.001, r = 0.673 for IFN-γ+CD4+T cells; P = 0.007, r = 0.581 for TNF-α+CD4+T cells) (Fig 5A). In addition, the frequency of the granzyme B+CD4+T cells was also positively associated with the frequency of IFN-γ+CTLs (P = 0.041, r = 0.460) (Fig 5A), suggesting that ThGzmB+ cells are potential cytolytic effector cell subsets against HTNV infection.

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