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Splenic CD11c+ cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria.

Bao LQ, Nhi DM, Huy NT, Kikuchi M, Yanagi T, Hamano S, Hirayama K - Malar. J. (2015)

Bottom Line: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells.The spleens of infected semi-immune mice were collected for flow cytometry analysis.CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunogenetics, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan. lamquocbao@nagasaki-u.ac.jp.

ABSTRACT

Background: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells. Previously, mice semi-immune to malaria was developed. Three cycles of infection and cure ('three-cure') were required to protect mice against Plasmodium berghei (ANKA strain) infection.

Methods: C57BL/6 J mice underwent three cycles of P. berghei infection and drug-cure to become semi-immune. The spleens of infected semi-immune mice were collected for flow cytometry analysis. CD11c(+) cells of semi-immune mice were isolated and transferred into naïve mice which were subsequently challenged and followed up by survival and parasitaemia.

Results: The percentages of splenic CD4(+) and CD11c(+) cells were increased in semi-immune mice on day 7 post-infection. The proportion and number of B220(+)CD11c(+)low cells (plasmacytoid dendritic cells, DCs) was higher in semi-immune, three-cure mice than in their naïve littermates on day 7 post-infection (2.6 vs 1.1% and 491,031 vs 149,699, respectively). In adoptive transfer experiment, three months after the third cured P. berghei infection, splenic CD11c(+) DCs of non-infected, semi-immune, three-cure mice slowed Plasmodium proliferation and decreased the death rate due to neurological pathology in recipient mice. In addition, anti-P. berghei IgG1 level was higher in mice transferred with CD11c(+) cells of semi-immune, three-cure mice than mice transferred with CD11c(+) cells of naïve counterparts.

Conclusion: CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

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The proportion of B220(+)CD11c(+)low cells was higher and the size of CD11c(+)hi cells was enhanced on day 7 post-infection in semi-immune mice challenged three months after the third exposure to malaria. (A) Median percentages of splenic CD4(+), CD8(+) and CD11c(+) cells on day 7 post-infection (±interquartile range) (n = 6-7 mice/group). (B) Median percentages and number of splenic B220(+)CD11c(+)low cells and B220(−)CD11c(+)hi cells on day 7 post-infection (±interquartile range) (n = 4 mice/group). Plots show the gating strategy and data for representatives of these cells on day 7 post-infection in semi-immune and naïve mice. (C) Relative median size of splenic CD11c(+)hi cells on day 7 post-infection (±interquartile range) (n = 4 mice/group). Representative histograms regarding the size of CD11c(+)hi cells in semi-immune (black) and naïve (red) mice on day 0 and day 7 post-infection are shown. Data are pooled from two independent experiments (A, B) or representative of two independent experiments (C). *P < 0.05, Mann–Whitney U test.
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Fig1: The proportion of B220(+)CD11c(+)low cells was higher and the size of CD11c(+)hi cells was enhanced on day 7 post-infection in semi-immune mice challenged three months after the third exposure to malaria. (A) Median percentages of splenic CD4(+), CD8(+) and CD11c(+) cells on day 7 post-infection (±interquartile range) (n = 6-7 mice/group). (B) Median percentages and number of splenic B220(+)CD11c(+)low cells and B220(−)CD11c(+)hi cells on day 7 post-infection (±interquartile range) (n = 4 mice/group). Plots show the gating strategy and data for representatives of these cells on day 7 post-infection in semi-immune and naïve mice. (C) Relative median size of splenic CD11c(+)hi cells on day 7 post-infection (±interquartile range) (n = 4 mice/group). Representative histograms regarding the size of CD11c(+)hi cells in semi-immune (black) and naïve (red) mice on day 0 and day 7 post-infection are shown. Data are pooled from two independent experiments (A, B) or representative of two independent experiments (C). *P < 0.05, Mann–Whitney U test.

Mentions: It was found that the percentage of splenic CD4(+) and CD11c(+) cells in semi-immune mice on day 7 post-infection was significantly higher than in infected naïve counterparts (Figure 1A), suggesting a potentially protective cooperation of CD4(+) and CD11c(+) cells against Plasmodium infection. Meanwhile, no significant difference in proportion of CD8(+) cells was observed between these two groups of mice (Figure 1A). Thus, this study was carried out with the hypothesis that CD11c(+) cells from semi-immune mice contributed to immunity against ECM. In murine malaria infection, splenic CD11c(+) cells are considered as splenic CD11c(+) DCs [20]. The role of DCs in prolonged suppression against malaria is still unclear. Hence, the anti-malaria capacity of CD11c(+) DCs and their subtypes was investigated from semi-immune mice in long term after the last immunization. B220(+)CD11c(+)low cells, named as plasmacytoid DCs [21,22], play a critical role in immunity to malaria [21] and in improving the function of conventional DCs [23]. The distribution of this DC subtype in the spleen of semi-immune mice was, therefore, examined. Three months after the third cured malaria infection, B220(+)CD11c(+)low cells in CD19(−) gate accounted for a significantly higher percentage and showed a greater number of cells on day 7 post-infection in infected semi-immune mice than in naïve littermates (2.6 and 1.1%; 491,031 and 149,699, respectively; P < 0.05) (Figure 1B). Meanwhile, no differences in the proportion or number of B220(−)CD11c(+)hi cells (conventional DCs) was observed between these two groups (1.3 and 1.4%; 222,096 and 127,144, respectively) (Figure 1B). The increase in the proportion of plasmacytoid DCs in semi-immune mice probably enhanced the activation of conventional DCs and, therefore, stimulated the proliferation of T cells, leading to parasite clearance.Figure 1


Splenic CD11c+ cells derived from semi-immune mice protect naïve mice against experimental cerebral malaria.

Bao LQ, Nhi DM, Huy NT, Kikuchi M, Yanagi T, Hamano S, Hirayama K - Malar. J. (2015)

The proportion of B220(+)CD11c(+)low cells was higher and the size of CD11c(+)hi cells was enhanced on day 7 post-infection in semi-immune mice challenged three months after the third exposure to malaria. (A) Median percentages of splenic CD4(+), CD8(+) and CD11c(+) cells on day 7 post-infection (±interquartile range) (n = 6-7 mice/group). (B) Median percentages and number of splenic B220(+)CD11c(+)low cells and B220(−)CD11c(+)hi cells on day 7 post-infection (±interquartile range) (n = 4 mice/group). Plots show the gating strategy and data for representatives of these cells on day 7 post-infection in semi-immune and naïve mice. (C) Relative median size of splenic CD11c(+)hi cells on day 7 post-infection (±interquartile range) (n = 4 mice/group). Representative histograms regarding the size of CD11c(+)hi cells in semi-immune (black) and naïve (red) mice on day 0 and day 7 post-infection are shown. Data are pooled from two independent experiments (A, B) or representative of two independent experiments (C). *P < 0.05, Mann–Whitney U test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Fig1: The proportion of B220(+)CD11c(+)low cells was higher and the size of CD11c(+)hi cells was enhanced on day 7 post-infection in semi-immune mice challenged three months after the third exposure to malaria. (A) Median percentages of splenic CD4(+), CD8(+) and CD11c(+) cells on day 7 post-infection (±interquartile range) (n = 6-7 mice/group). (B) Median percentages and number of splenic B220(+)CD11c(+)low cells and B220(−)CD11c(+)hi cells on day 7 post-infection (±interquartile range) (n = 4 mice/group). Plots show the gating strategy and data for representatives of these cells on day 7 post-infection in semi-immune and naïve mice. (C) Relative median size of splenic CD11c(+)hi cells on day 7 post-infection (±interquartile range) (n = 4 mice/group). Representative histograms regarding the size of CD11c(+)hi cells in semi-immune (black) and naïve (red) mice on day 0 and day 7 post-infection are shown. Data are pooled from two independent experiments (A, B) or representative of two independent experiments (C). *P < 0.05, Mann–Whitney U test.
Mentions: It was found that the percentage of splenic CD4(+) and CD11c(+) cells in semi-immune mice on day 7 post-infection was significantly higher than in infected naïve counterparts (Figure 1A), suggesting a potentially protective cooperation of CD4(+) and CD11c(+) cells against Plasmodium infection. Meanwhile, no significant difference in proportion of CD8(+) cells was observed between these two groups of mice (Figure 1A). Thus, this study was carried out with the hypothesis that CD11c(+) cells from semi-immune mice contributed to immunity against ECM. In murine malaria infection, splenic CD11c(+) cells are considered as splenic CD11c(+) DCs [20]. The role of DCs in prolonged suppression against malaria is still unclear. Hence, the anti-malaria capacity of CD11c(+) DCs and their subtypes was investigated from semi-immune mice in long term after the last immunization. B220(+)CD11c(+)low cells, named as plasmacytoid DCs [21,22], play a critical role in immunity to malaria [21] and in improving the function of conventional DCs [23]. The distribution of this DC subtype in the spleen of semi-immune mice was, therefore, examined. Three months after the third cured malaria infection, B220(+)CD11c(+)low cells in CD19(−) gate accounted for a significantly higher percentage and showed a greater number of cells on day 7 post-infection in infected semi-immune mice than in naïve littermates (2.6 and 1.1%; 491,031 and 149,699, respectively; P < 0.05) (Figure 1B). Meanwhile, no differences in the proportion or number of B220(−)CD11c(+)hi cells (conventional DCs) was observed between these two groups (1.3 and 1.4%; 222,096 and 127,144, respectively) (Figure 1B). The increase in the proportion of plasmacytoid DCs in semi-immune mice probably enhanced the activation of conventional DCs and, therefore, stimulated the proliferation of T cells, leading to parasite clearance.Figure 1

Bottom Line: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells.The spleens of infected semi-immune mice were collected for flow cytometry analysis.CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunogenetics, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan. lamquocbao@nagasaki-u.ac.jp.

ABSTRACT

Background: Immunity to malaria requires innate, adaptive immune responses and Plasmodium-specific memory cells. Previously, mice semi-immune to malaria was developed. Three cycles of infection and cure ('three-cure') were required to protect mice against Plasmodium berghei (ANKA strain) infection.

Methods: C57BL/6 J mice underwent three cycles of P. berghei infection and drug-cure to become semi-immune. The spleens of infected semi-immune mice were collected for flow cytometry analysis. CD11c(+) cells of semi-immune mice were isolated and transferred into naïve mice which were subsequently challenged and followed up by survival and parasitaemia.

Results: The percentages of splenic CD4(+) and CD11c(+) cells were increased in semi-immune mice on day 7 post-infection. The proportion and number of B220(+)CD11c(+)low cells (plasmacytoid dendritic cells, DCs) was higher in semi-immune, three-cure mice than in their naïve littermates on day 7 post-infection (2.6 vs 1.1% and 491,031 vs 149,699, respectively). In adoptive transfer experiment, three months after the third cured P. berghei infection, splenic CD11c(+) DCs of non-infected, semi-immune, three-cure mice slowed Plasmodium proliferation and decreased the death rate due to neurological pathology in recipient mice. In addition, anti-P. berghei IgG1 level was higher in mice transferred with CD11c(+) cells of semi-immune, three-cure mice than mice transferred with CD11c(+) cells of naïve counterparts.

Conclusion: CD11c(+) cells of semi-immune mice protect against experimental cerebral malaria three months after the third cured malaria, potentially through protective plasmacytoid DCs and enhanced production of malaria-specific antibody.

Show MeSH
Related in: MedlinePlus