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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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FeD Mice have Modulated Frequencies of Splenic NK Cells and Tregs Early During the Infection.Representative flow cytometric dot plots of NK cells (a) and the percentage of NK cells (b) on day 3 and day 7 post-infection. Representative flow cytometric dot plots of Tregs (c) and the percentage of Tregs after gating on CD4+ T cells (d) on day 3 and day 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. On day 3 post-infection, n = 6 for control mice and n = 5 for FeD mice, except for Tregs, where n = 5 for the control mice. On day 7 post-infection, n = 6 for control mice and n = 6 for FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 ** P < 0.01), were determined by unpaired Student’s t-test.
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pone.0118451.g008: FeD Mice have Modulated Frequencies of Splenic NK Cells and Tregs Early During the Infection.Representative flow cytometric dot plots of NK cells (a) and the percentage of NK cells (b) on day 3 and day 7 post-infection. Representative flow cytometric dot plots of Tregs (c) and the percentage of Tregs after gating on CD4+ T cells (d) on day 3 and day 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. On day 3 post-infection, n = 6 for control mice and n = 5 for FeD mice, except for Tregs, where n = 5 for the control mice. On day 7 post-infection, n = 6 for control mice and n = 6 for FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 ** P < 0.01), were determined by unpaired Student’s t-test.

Mentions: Finally, we were interested in determining if iron supplementation affected other factors that might augment protection. Both NK cells and Tregs have been shown to influence the development of ECM. Depletion of NK cells using an anti-asialo GM1 antibody has been shown to inhibit T cell chemotaxis to the brain by attenuating CXCR3 expression on splenic T cells [19]. Additionally, the in vivo expansion of Tregs was observed to prevent conventional T cell accumulation in the brain during ECM through a CTLA-4-dependent mechanism [20]. This study did not examine the expression of CXCR3 on conventional T cells; however, adoptive transfer of Tregs has previously been demonstrated to mitigate CXCR3 expression on CD4+ T cells [21]. Therefore, the frequencies of splenic NK cells and Tregs were measured to determine if iron conferred protection by modulating the percentages of these cell types. On day 3 post-infection, the percentage of splenic NK cells was markedly decreased in the FeD mice (Fig. 8A,B). The percentage of NK cells decreased in both groups from day 3 post-infection to day 7 post-infection and the percentage of NK cells in the FeD mice was the same as the control mice on day 7 post-infection (Fig. 8A,B). The percentage of Tregs was increased in the FeD mice on day 3 post-infection (Fig. 8C,D). This trend was also observed on day 7 post-infection; however, the difference was no longer significant (Fig. 8C,D). Therefore, it appears that the modulated frequencies of NK cells and Tregs are associated with decreased ECM pathology in the FeD mice.


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)

FeD Mice have Modulated Frequencies of Splenic NK Cells and Tregs Early During the Infection.Representative flow cytometric dot plots of NK cells (a) and the percentage of NK cells (b) on day 3 and day 7 post-infection. Representative flow cytometric dot plots of Tregs (c) and the percentage of Tregs after gating on CD4+ T cells (d) on day 3 and day 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. On day 3 post-infection, n = 6 for control mice and n = 5 for FeD mice, except for Tregs, where n = 5 for the control mice. On day 7 post-infection, n = 6 for control mice and n = 6 for FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 ** P < 0.01), 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.g008: FeD Mice have Modulated Frequencies of Splenic NK Cells and Tregs Early During the Infection.Representative flow cytometric dot plots of NK cells (a) and the percentage of NK cells (b) on day 3 and day 7 post-infection. Representative flow cytometric dot plots of Tregs (c) and the percentage of Tregs after gating on CD4+ T cells (d) on day 3 and day 7 post-infection. The numbers shown on the dot plots indicate the mean percentage of cells inside the gate ± S.E.M. On day 3 post-infection, n = 6 for control mice and n = 5 for FeD mice, except for Tregs, where n = 5 for the control mice. On day 7 post-infection, n = 6 for control mice and n = 6 for FeD mice. FeD = iron dextran, PBS = control. Statistically significant differences, shown by asterisks (* P < 0.05 ** P < 0.01), were determined by unpaired Student’s t-test.
Mentions: Finally, we were interested in determining if iron supplementation affected other factors that might augment protection. Both NK cells and Tregs have been shown to influence the development of ECM. Depletion of NK cells using an anti-asialo GM1 antibody has been shown to inhibit T cell chemotaxis to the brain by attenuating CXCR3 expression on splenic T cells [19]. Additionally, the in vivo expansion of Tregs was observed to prevent conventional T cell accumulation in the brain during ECM through a CTLA-4-dependent mechanism [20]. This study did not examine the expression of CXCR3 on conventional T cells; however, adoptive transfer of Tregs has previously been demonstrated to mitigate CXCR3 expression on CD4+ T cells [21]. Therefore, the frequencies of splenic NK cells and Tregs were measured to determine if iron conferred protection by modulating the percentages of these cell types. On day 3 post-infection, the percentage of splenic NK cells was markedly decreased in the FeD mice (Fig. 8A,B). The percentage of NK cells decreased in both groups from day 3 post-infection to day 7 post-infection and the percentage of NK cells in the FeD mice was the same as the control mice on day 7 post-infection (Fig. 8A,B). The percentage of Tregs was increased in the FeD mice on day 3 post-infection (Fig. 8C,D). This trend was also observed on day 7 post-infection; however, the difference was no longer significant (Fig. 8C,D). Therefore, it appears that the modulated frequencies of NK cells and Tregs are associated with decreased ECM pathology in the FeD mice.

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