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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

Distribution of 15-mer T-cell epitopes and frequency of recognition over the HTNV-Gn/Gc full sequence.Each bar represents a distinctive HTNV-Gn/Gc T-cell epitope, with the length of the bar indicating the percentage of subjects targeting this epitope. Bars above the line correspond to responses at acute stage in the cohort with mild or moderate infection (n = 31), and the bars below the line represent responses detected in acute phase in persons with severe or critical infections (n = 39). The 20 epitopes with the start amino acid number of each peptide indicated were defined as the immunodominant epitopes, which were frequently recognized (≥10% of the total positive responding subjects, n = 70) in the patients. aa, amino acid.
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ppat.1004788.g001: Distribution of 15-mer T-cell epitopes and frequency of recognition over the HTNV-Gn/Gc full sequence.Each bar represents a distinctive HTNV-Gn/Gc T-cell epitope, with the length of the bar indicating the percentage of subjects targeting this epitope. Bars above the line correspond to responses at acute stage in the cohort with mild or moderate infection (n = 31), and the bars below the line represent responses detected in acute phase in persons with severe or critical infections (n = 39). The 20 epitopes with the start amino acid number of each peptide indicated were defined as the immunodominant epitopes, which were frequently recognized (≥10% of the total positive responding subjects, n = 70) in the patients. aa, amino acid.

Mentions: To examine the specific T-cell responses to HTNV-Gn/Gc in HFRS patients, we first screened the T-cell epitopes on HTNV-Gn/Gc. The majority of the participants in this cohort displayed reactive T-cell responses against HTNV-Gn/Gc. Notably, 73.7% (70/95) of the HFRS individuals were responders recognizing at least 1 peptide pool. Among the 70 participants displaying positive responses to HTNV-Gn/Gc, a median of 4 (range 1–11) target peptide pools were detected in each HFRS individual, with a median spot magnitude of 609 (range, 95–4,911) spot-forming cells (SFC)/106 peripheral blood mononuclear cells (PBMCs) against total peptide pools. All peptide pools showed positive responses, among which four peptide pools (P5, P12, P21 and P25) were frequently detected in more than 30% of the subjects, and 7 peptide pools (P17 to P23) contained the most frequently identified HTNV-Gn/Gc reactive T-cell peptides eliciting the strongest responses (S1 Table). Next, we analyzed the positive responses at the single peptide level to identify the T-cell epitopes on HTNV-Gn/Gc. Overall, the single peptide-specific T-cell responses were widely distributed across the primary structure of HTNV-Gn/Gc. Approximately, 155 of the 281 peptides (55.2%) were recognized by at least one person, and among these, 20 peptides were frequently targeted as the immunodominant epitopes in more than 10% of HFRS individuals with diverse HLA backgrounds (Fig 1, Table 1). A median of 6 peptides (range, 1–25) were targeted in a single individual, and the strength of some individual epitope-specific responses reached 1,546 SFC/106 PBMCs. Moreover, to identify a more precise estimation of the epitope-specific T-cell responses, the distribution of ex vivo CD4+ and CD8+T-cell epitopes across the HTNV-Gn/Gc was defined in 25 positive response HFRS patients with sufficient PBMC samples (Fig 2). The detected responses to 28 15-mer peptides were entirely CD4+T-cell dependent, indicating that these peptides were CD4+T-cell epitopes on HTNV-Gc/Gc. Whereas, the CD8+T-cell depletion completely abrogated the interferon (IFN) -γ responses in another 21 15-mer HTNV-Gc/Gc epitopes, confirming CD8+T cells as the source of these epitope-specific responses, and these peptides might contain the 9 or 10-mer HTNV-Gc/Gc CTL epitopes. Moreover, we identified 30 additional peptides that could induce both CD4+ and CD8+T-cell responses against HTNV-Gc/Gc.


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)

Distribution of 15-mer T-cell epitopes and frequency of recognition over the HTNV-Gn/Gc full sequence.Each bar represents a distinctive HTNV-Gn/Gc T-cell epitope, with the length of the bar indicating the percentage of subjects targeting this epitope. Bars above the line correspond to responses at acute stage in the cohort with mild or moderate infection (n = 31), and the bars below the line represent responses detected in acute phase in persons with severe or critical infections (n = 39). The 20 epitopes with the start amino acid number of each peptide indicated were defined as the immunodominant epitopes, which were frequently recognized (≥10% of the total positive responding subjects, n = 70) in the patients. aa, amino acid.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383613&req=5

ppat.1004788.g001: Distribution of 15-mer T-cell epitopes and frequency of recognition over the HTNV-Gn/Gc full sequence.Each bar represents a distinctive HTNV-Gn/Gc T-cell epitope, with the length of the bar indicating the percentage of subjects targeting this epitope. Bars above the line correspond to responses at acute stage in the cohort with mild or moderate infection (n = 31), and the bars below the line represent responses detected in acute phase in persons with severe or critical infections (n = 39). The 20 epitopes with the start amino acid number of each peptide indicated were defined as the immunodominant epitopes, which were frequently recognized (≥10% of the total positive responding subjects, n = 70) in the patients. aa, amino acid.
Mentions: To examine the specific T-cell responses to HTNV-Gn/Gc in HFRS patients, we first screened the T-cell epitopes on HTNV-Gn/Gc. The majority of the participants in this cohort displayed reactive T-cell responses against HTNV-Gn/Gc. Notably, 73.7% (70/95) of the HFRS individuals were responders recognizing at least 1 peptide pool. Among the 70 participants displaying positive responses to HTNV-Gn/Gc, a median of 4 (range 1–11) target peptide pools were detected in each HFRS individual, with a median spot magnitude of 609 (range, 95–4,911) spot-forming cells (SFC)/106 peripheral blood mononuclear cells (PBMCs) against total peptide pools. All peptide pools showed positive responses, among which four peptide pools (P5, P12, P21 and P25) were frequently detected in more than 30% of the subjects, and 7 peptide pools (P17 to P23) contained the most frequently identified HTNV-Gn/Gc reactive T-cell peptides eliciting the strongest responses (S1 Table). Next, we analyzed the positive responses at the single peptide level to identify the T-cell epitopes on HTNV-Gn/Gc. Overall, the single peptide-specific T-cell responses were widely distributed across the primary structure of HTNV-Gn/Gc. Approximately, 155 of the 281 peptides (55.2%) were recognized by at least one person, and among these, 20 peptides were frequently targeted as the immunodominant epitopes in more than 10% of HFRS individuals with diverse HLA backgrounds (Fig 1, Table 1). A median of 6 peptides (range, 1–25) were targeted in a single individual, and the strength of some individual epitope-specific responses reached 1,546 SFC/106 PBMCs. Moreover, to identify a more precise estimation of the epitope-specific T-cell responses, the distribution of ex vivo CD4+ and CD8+T-cell epitopes across the HTNV-Gn/Gc was defined in 25 positive response HFRS patients with sufficient PBMC samples (Fig 2). The detected responses to 28 15-mer peptides were entirely CD4+T-cell dependent, indicating that these peptides were CD4+T-cell epitopes on HTNV-Gc/Gc. Whereas, the CD8+T-cell depletion completely abrogated the interferon (IFN) -γ responses in another 21 15-mer HTNV-Gc/Gc epitopes, confirming CD8+T cells as the source of these epitope-specific responses, and these peptides might contain the 9 or 10-mer HTNV-Gc/Gc CTL epitopes. Moreover, we identified 30 additional peptides that could induce both CD4+ and CD8+T-cell responses against HTNV-Gc/Gc.

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