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. 2011 Feb 10;7(2):e1001281.
doi: 10.1371/journal.ppat.1001281.

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

Jiraprapa Wipasa  1 , Lucy Okell, Supachai Sakkhachornphop, Chaisuree Suphavilai, Kriangkrai Chawansuntati, Witaya Liewsaree, Julius C R Hafalla, Eleanor M Riley
Affiliations

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

Jiraprapa Wipasa et al. PLoS Pathog. .

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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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Flow cytometric characterization, frequencies and longevity of memory CD4 T cells proliferating in response to PfSE.
CFSE-labeled PBMCs were stimulated with no antigen, PfSE, PPD or PHA for 6 days. Cells were harvested and stained with fluorochrome-conjugated anti-CD3, CD4 or CD45RO mAbs. (A) PBMC were gated by forward and side scatter and the CD3+ and CD4+ T lymphocyte population was identified; (B) CFSE expression in CD4+ T cells. CD3+ CD4+ T cells were gated and CFSE expression examined in relation to CD45RO (C) expression. The plots demonstrate the results for one representative subject known to have been infected previously by P. falciparum. Percentages of proliferating CD45RO+ CD4+ T cells (CFSElow) among (D) city (circles), Rural 1 (triangles) and Rural 2 (reverse triangles) subjects and (E) between individuals who had been infected with P. falciparum and P. vivax. Mean ±95% confidence interval is shown for each group.
Figure 2
Figure 2. 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.
Figure 3
Figure 3. IL-10 concentrations in 6 day cell culture supernatants.
(A) Concentration (mean ±95% CI) of IL-10 in 6 day, PfSE-stimulated culture supernatants at recruitment. IL-10 concentrations in 6 day, PfSE-stimulated culture supernatants at recruitment and 12 months later in Rural 1 (B) and Rural 2 (C) 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 the 6 day IL-10 response to PfSE over time in P. falciparum-exposed (D) and P. vivax-exposed (E) subjects. Solid lines represent best fit regression lines estimating the rates of decline of the 6 day cytokine responses over time and dashed lines represent the 95% CI.
Figure 4
Figure 4. Association between memory T cell responses and humoral immunity to malaria.
(A-C) Immediate IFN-γ responses in rural individuals with (Ab pos) or without (Ab neg) antibodies to (A) PfSE or (B) recombinant malaria antigens, or (C) individuals with or without detectable memory B cells specific for P. falciparum antigens. 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. (D – F) 6 day IL-10 responses in rural individuals with or without antibodies to (D) PfSE or (E) recombinant malaria antigens, or (F) individuals with or without detectable memory B cells specific for P. falciparum antigens. [Horizontal line  =  median; box  = 25th and 75th percentiles; whiskers  =  minimum and maximum values]. Mann-Whitney U test was used to analyse differences between groups.
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