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Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis.

Van Den Ham KM, Shio MT, Rainone A, Fournier S, Krawczyk CM, Olivier M - PLoS ONE (2015)

Bottom Line: Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain.CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet.Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada; McGill International TB Centre, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

ABSTRACT
Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain.

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Sequestration of CD4+ and CD8+ T Cells in the Brain is Reduced in FeD Mice.The total number of cells recovered after isolation (a), the total number (b) and percentage (c) of CD8+ T cells after gating on infiltrating leukocytes (CD45+CD11blo-hi), representative flow cytometric dot plots of CD4+ and CD8+ T cells after gating on infiltrating leukocytes (d), and the total number (e) and percentage (f) of CD4+ T cells after gating on infiltrating leukocytes, on day 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. n = 5 mice were used for each group. UI = uninfected, I = infected, FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 and *** P < 0.001), were determined by unpaired Student’s t-test.
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pone.0118451.g005: Sequestration of CD4+ and CD8+ T Cells in the Brain is Reduced in FeD Mice.The total number of cells recovered after isolation (a), the total number (b) and percentage (c) of CD8+ T cells after gating on infiltrating leukocytes (CD45+CD11blo-hi), representative flow cytometric dot plots of CD4+ and CD8+ T cells after gating on infiltrating leukocytes (d), and the total number (e) and percentage (f) of CD4+ T cells after gating on infiltrating leukocytes, on day 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. n = 5 mice were used for each group. UI = uninfected, I = infected, FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 and *** P < 0.001), were determined by unpaired Student’s t-test.

Mentions: The sequestration of CD4+ and CD8+ T cells to the brain was examined on day 7 post-infection to determine if the decreased expression of trafficking-associated genes correlated with a reduction in the chemotaxis of T cells to the brain. Infiltration of cells into the brain, as represented by the number of cells recovered after cell isolation, was significantly decreased in the FeD mice compared to the control mice after infection (Fig. 5A). A slight increase in cell accumulation in the infected FeD mice compared to the uninfected FeD mice was measured, indicating that immune cell recruitment was not completely abrogated by parenteral iron supplementation. Furthermore, the infiltration of cells was not changed between the uninfected control and the uninfected FeD mice, suggesting that iron-mediated attenuation of immune cell sequestration only occurs after infection. There was a marked decrease in the number of accumulated CD8+ T cells in the FeD mice after infection, and no change between the control and FeD mice without infection (Fig. 5B). Moreover, the number of CD8+ T cells was increased in the infected FeD mice compared to the uninfected FeD mice. Similar results were obtained for the percentage of CD8+ T cells (Fig. 5C,D). A decrease in the total number of CD4+ T cells sequestered in the brain of the infected FeD mice compared to the infected control mice was observed (Fig. 5E). No difference in the accumulation of CD4+ T cells was detected between the control and FeD mice without infection and a minor increase in the number of CD4+ T cells was measured in the infected FeD mice compared to the uninfected FeD mice. Iron supplementation did not change the percentage of CD4+ T cells, but the percentage decreased during infection in the control mice (Fig. 5D,F).


Iron prevents the development of experimental cerebral malaria by attenuating CXCR3-mediated T cell chemotaxis.

Van Den Ham KM, Shio MT, Rainone A, Fournier S, Krawczyk CM, Olivier M - PLoS ONE (2015)

Sequestration of CD4+ and CD8+ T Cells in the Brain is Reduced in FeD Mice.The total number of cells recovered after isolation (a), the total number (b) and percentage (c) of CD8+ T cells after gating on infiltrating leukocytes (CD45+CD11blo-hi), representative flow cytometric dot plots of CD4+ and CD8+ T cells after gating on infiltrating leukocytes (d), and the total number (e) and percentage (f) of CD4+ T cells after gating on infiltrating leukocytes, on day 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. n = 5 mice were used for each group. UI = uninfected, I = infected, FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 and *** P < 0.001), were determined by unpaired Student’s t-test.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4359107&req=5

pone.0118451.g005: Sequestration of CD4+ and CD8+ T Cells in the Brain is Reduced in FeD Mice.The total number of cells recovered after isolation (a), the total number (b) and percentage (c) of CD8+ T cells after gating on infiltrating leukocytes (CD45+CD11blo-hi), representative flow cytometric dot plots of CD4+ and CD8+ T cells after gating on infiltrating leukocytes (d), and the total number (e) and percentage (f) of CD4+ T cells after gating on infiltrating leukocytes, on day 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. n = 5 mice were used for each group. UI = uninfected, I = infected, FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 and *** P < 0.001), were determined by unpaired Student’s t-test.
Mentions: The sequestration of CD4+ and CD8+ T cells to the brain was examined on day 7 post-infection to determine if the decreased expression of trafficking-associated genes correlated with a reduction in the chemotaxis of T cells to the brain. Infiltration of cells into the brain, as represented by the number of cells recovered after cell isolation, was significantly decreased in the FeD mice compared to the control mice after infection (Fig. 5A). A slight increase in cell accumulation in the infected FeD mice compared to the uninfected FeD mice was measured, indicating that immune cell recruitment was not completely abrogated by parenteral iron supplementation. Furthermore, the infiltration of cells was not changed between the uninfected control and the uninfected FeD mice, suggesting that iron-mediated attenuation of immune cell sequestration only occurs after infection. There was a marked decrease in the number of accumulated CD8+ T cells in the FeD mice after infection, and no change between the control and FeD mice without infection (Fig. 5B). Moreover, the number of CD8+ T cells was increased in the infected FeD mice compared to the uninfected FeD mice. Similar results were obtained for the percentage of CD8+ T cells (Fig. 5C,D). A decrease in the total number of CD4+ T cells sequestered in the brain of the infected FeD mice compared to the infected control mice was observed (Fig. 5E). No difference in the accumulation of CD4+ T cells was detected between the control and FeD mice without infection and a minor increase in the number of CD4+ T cells was measured in the infected FeD mice compared to the uninfected FeD mice. Iron supplementation did not change the percentage of CD4+ T cells, but the percentage decreased during infection in the control mice (Fig. 5D,F).

Bottom Line: Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain.CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet.Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada; McGill International TB Centre, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.

ABSTRACT
Cerebral malaria is a severe neurological complication of Plasmodium falciparum infection. Previous studies have suggested that iron overload can suppress the generation of a cytotoxic immune response; however, the effect of iron on experimental cerebral malaria (ECM) is yet unknown. Here we determined that the incidence of ECM was markedly reduced in mice treated with iron dextran. Protection was concomitant with a significant decrease in the sequestration of CD4+ and CD8+ T cells within the brain. CD4+ T cells demonstrated markedly decreased CXCR3 expression and had reduced IFNγ-responsiveness, as indicated by mitigated expression of IFNγR2 and T-bet. Additional analysis of the splenic cell populations indicated that parenteral iron supplementation was also associated with a decrease in NK cells and increase in regulatory T cells. Altogether, these results suggest that iron is able to inhibit ECM pathology by attenuating the capacity of T cells to migrate to the brain.

Show MeSH
Related in: MedlinePlus