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Short-lived IFN-γ effector responses, but long-lived IL-10 memory responses, to malaria in an area of low malaria endemicity.

Wipasa J, Okell L, Sakkhachornphop S, Suphavilai C, Chawansuntati K, Liewsaree W, Hafalla JC, Riley EM - PLoS Pathog. (2011)

Bottom Line: The number of IFN-γ-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9-10.3) years.In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years.The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development.

View Article: PubMed Central - PubMed

Affiliation: Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.

ABSTRACT
Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we analysed malaria-specific CD4+ T cell responses of individuals living in an area of low malaria transmission in northern Thailand, who had had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years. CD4+ T cell effector memory (CD45RO+) IFN-γ (24 hours ex vivo restimulation) and cultured IL-10 (6 day secretion into culture supernatant) responses to malaria schizont antigens were detected only in malaria-exposed subjects and were more prominent in subjects with long-lived antibodies or memory B cells specific to malaria antigens. The number of IFN-γ-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9-10.3) years. In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years. The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development.

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Immediate IFN-γ and IL-10 production by effector memory CD4 T cells.PBMCs were stimulated with no antigen, PfSE, PPD or PHA for 20 hours. Cells were harvested and stained with fluorochrome-conjugated anti-CD3, CD4, CD45RO, IFN-γ or IL-10 mAbs. (A) PBMC were gated by forward and side scatter and the CD3+ and CD4+ T lymphocyte population was identified. IFN-γ and IL-10 production in CD45RO+ populations were then determined. The plots demonstrate the results for one representative subject known to have been infected previously by P. falciparum. (B) Fold increase (mean ±95% CI) in IFN-γ production in response to PfSE (compared with cells cultured without antigen) at recruitment for each subject. Immediate IFN-γ response at recruitment compared to at 12 months later in Rural 1 (C) and Rural 2 (D) subjects. [Horizontal line  =  median; box  = 25th and 75th percentiles; whiskers  =  minimum and maximum values]. Paired t-tests were used to analyse differences between the two time points. Best-fit regression analysis of changes in fold increase of immediate IFN-γ producing CD45RO+ CD4+ T cells in response to PfSE over time in P. falciparum-exposed (E) and P. vivax-exposed (F) subjects. Solid lines represent best fit regression lines estimating the rates of decline of immediate cytokine responses over time and dashed lines represent the 95% CI. The median percentages of immediate IFN-γ producing CD45RO+ CD4+ T cells in unstimulated control cultures were 0.029, 0.031 and 0.027 in naïve, Rural 1 and Rural 2 subjects, respectively.
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ppat-1001281-g002: Immediate IFN-γ and IL-10 production by effector memory CD4 T cells.PBMCs were stimulated with no antigen, PfSE, PPD or PHA for 20 hours. Cells were harvested and stained with fluorochrome-conjugated anti-CD3, CD4, CD45RO, IFN-γ or IL-10 mAbs. (A) PBMC were gated by forward and side scatter and the CD3+ and CD4+ T lymphocyte population was identified. IFN-γ and IL-10 production in CD45RO+ populations were then determined. The plots demonstrate the results for one representative subject known to have been infected previously by P. falciparum. (B) Fold increase (mean ±95% CI) in IFN-γ production in response to PfSE (compared with cells cultured without antigen) at recruitment for each subject. Immediate IFN-γ response at recruitment compared to at 12 months later in Rural 1 (C) and Rural 2 (D) subjects. [Horizontal line  =  median; box  = 25th and 75th percentiles; whiskers  =  minimum and maximum values]. Paired t-tests were used to analyse differences between the two time points. Best-fit regression analysis of changes in fold increase of immediate IFN-γ producing CD45RO+ CD4+ T cells in response to PfSE over time in P. falciparum-exposed (E) and P. vivax-exposed (F) subjects. Solid lines represent best fit regression lines estimating the rates of decline of immediate cytokine responses over time and dashed lines represent the 95% CI. The median percentages of immediate IFN-γ producing CD45RO+ CD4+ T cells in unstimulated control cultures were 0.029, 0.031 and 0.027 in naïve, Rural 1 and Rural 2 subjects, respectively.

Mentions: Since immunological memory depends on being able to mount a fast and effective response to infection, the number and/or function of effector memory cells is likely to be a more relevant indicator of an anamnestic response than simply the number or proportion of proliferating cells. We therefore examined the capacity of memory CD4+ T cells to produce the effector cytokine IFN-γ and the regulatory cytokine IL-10 in response to 24 hrs stimulation with PfSE or PPD. Representative flow cytometry plots showing intracellular IFN-γ and IL-10 among CD4+ CD45RO+ T cells are shown in Figure 2A. The number of IFN-γ+ or IL-10+ T cells in PfSE-stimulated cultures is shown as the fold increase compared with the number in unstimulated cultures.


Short-lived IFN-γ effector responses, but long-lived IL-10 memory responses, to malaria in an area of low malaria endemicity.

Wipasa J, Okell L, Sakkhachornphop S, Suphavilai C, Chawansuntati K, Liewsaree W, Hafalla JC, Riley EM - PLoS Pathog. (2011)

Immediate IFN-γ and IL-10 production by effector memory CD4 T cells.PBMCs were stimulated with no antigen, PfSE, PPD or PHA for 20 hours. Cells were harvested and stained with fluorochrome-conjugated anti-CD3, CD4, CD45RO, IFN-γ or IL-10 mAbs. (A) PBMC were gated by forward and side scatter and the CD3+ and CD4+ T lymphocyte population was identified. IFN-γ and IL-10 production in CD45RO+ populations were then determined. The plots demonstrate the results for one representative subject known to have been infected previously by P. falciparum. (B) Fold increase (mean ±95% CI) in IFN-γ production in response to PfSE (compared with cells cultured without antigen) at recruitment for each subject. Immediate IFN-γ response at recruitment compared to at 12 months later in Rural 1 (C) and Rural 2 (D) subjects. [Horizontal line  =  median; box  = 25th and 75th percentiles; whiskers  =  minimum and maximum values]. Paired t-tests were used to analyse differences between the two time points. Best-fit regression analysis of changes in fold increase of immediate IFN-γ producing CD45RO+ CD4+ T cells in response to PfSE over time in P. falciparum-exposed (E) and P. vivax-exposed (F) subjects. Solid lines represent best fit regression lines estimating the rates of decline of immediate cytokine responses over time and dashed lines represent the 95% CI. The median percentages of immediate IFN-γ producing CD45RO+ CD4+ T cells in unstimulated control cultures were 0.029, 0.031 and 0.027 in naïve, Rural 1 and Rural 2 subjects, respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3037361&req=5

ppat-1001281-g002: Immediate IFN-γ and IL-10 production by effector memory CD4 T cells.PBMCs were stimulated with no antigen, PfSE, PPD or PHA for 20 hours. Cells were harvested and stained with fluorochrome-conjugated anti-CD3, CD4, CD45RO, IFN-γ or IL-10 mAbs. (A) PBMC were gated by forward and side scatter and the CD3+ and CD4+ T lymphocyte population was identified. IFN-γ and IL-10 production in CD45RO+ populations were then determined. The plots demonstrate the results for one representative subject known to have been infected previously by P. falciparum. (B) Fold increase (mean ±95% CI) in IFN-γ production in response to PfSE (compared with cells cultured without antigen) at recruitment for each subject. Immediate IFN-γ response at recruitment compared to at 12 months later in Rural 1 (C) and Rural 2 (D) subjects. [Horizontal line  =  median; box  = 25th and 75th percentiles; whiskers  =  minimum and maximum values]. Paired t-tests were used to analyse differences between the two time points. Best-fit regression analysis of changes in fold increase of immediate IFN-γ producing CD45RO+ CD4+ T cells in response to PfSE over time in P. falciparum-exposed (E) and P. vivax-exposed (F) subjects. Solid lines represent best fit regression lines estimating the rates of decline of immediate cytokine responses over time and dashed lines represent the 95% CI. The median percentages of immediate IFN-γ producing CD45RO+ CD4+ T cells in unstimulated control cultures were 0.029, 0.031 and 0.027 in naïve, Rural 1 and Rural 2 subjects, respectively.
Mentions: Since immunological memory depends on being able to mount a fast and effective response to infection, the number and/or function of effector memory cells is likely to be a more relevant indicator of an anamnestic response than simply the number or proportion of proliferating cells. We therefore examined the capacity of memory CD4+ T cells to produce the effector cytokine IFN-γ and the regulatory cytokine IL-10 in response to 24 hrs stimulation with PfSE or PPD. Representative flow cytometry plots showing intracellular IFN-γ and IL-10 among CD4+ CD45RO+ T cells are shown in Figure 2A. The number of IFN-γ+ or IL-10+ T cells in PfSE-stimulated cultures is shown as the fold increase compared with the number in unstimulated cultures.

Bottom Line: The number of IFN-γ-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9-10.3) years.In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years.The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development.

View Article: PubMed Central - PubMed

Affiliation: Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.

ABSTRACT
Immunity to malaria is widely believed to wane in the absence of reinfection, but direct evidence for the presence or absence of durable immunological memory to malaria is limited. Here, we analysed malaria-specific CD4+ T cell responses of individuals living in an area of low malaria transmission in northern Thailand, who had had a documented clinical attack of P. falciparum and/or P. vivax in the past 6 years. CD4+ T cell effector memory (CD45RO+) IFN-γ (24 hours ex vivo restimulation) and cultured IL-10 (6 day secretion into culture supernatant) responses to malaria schizont antigens were detected only in malaria-exposed subjects and were more prominent in subjects with long-lived antibodies or memory B cells specific to malaria antigens. The number of IFN-γ-producing effector memory T cells declined significantly over the 12 months of the study, and with time since last documented malaria infection, with an estimated half life of the response of 3.3 (95% CI 1.9-10.3) years. In sharp contrast, IL-10 responses were sustained for many years after last known malaria infection with no significant decline over at least 6 years. The observations have clear implications for understanding the immunoepidemiology of naturally acquired malaria infections and for malaria vaccine development.

Show MeSH
Related in: MedlinePlus