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Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function.

Millington OR, Di Lorenzo C, Phillips RS, Garside P, Brewer JM - J. Biol. (2006)

Bottom Line: This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice.Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens.Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell) membranes, reproduces the effect of intact infected red blood cells on DCs.

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Affiliation: Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, UK. owain.millington@strath.ac.uk

ABSTRACT

Background: Dendritic cells (DCs) are central to the initiation and regulation of the adaptive immune response during infection. Modulation of DC function may therefore allow evasion of the immune system by pathogens. Significant depression of the host's systemic immune response to both concurrent infections and heterologous vaccines has been observed during malaria infection, but the mechanisms underlying this immune hyporesponsiveness are controversial.

Results: Here, we demonstrate that the blood stages of malaria infection induce a failure of DC function in vitro and in vivo, causing suboptimal activation of T cells involved in heterologous immune responses. This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice. Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens. Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell) membranes, reproduces the effect of intact infected red blood cells on DCs. Furthermore, hemozoin-containing DCs could be identified in T-cell areas of the spleen in vivo.

Conclusion: Plasmodium infection inhibits the induction of adaptive immunity to heterologous antigens by modulating DC function, providing a potential explanation for epidemiological studies linking endemic malaria with secondary infections and reduced vaccine efficacy.

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Modulation of DC activation in vivo during P. chabaudi infection. (a-c) Splenic CD11c+ DCs were isolated from P. chabaudi infected mice at various times (filled bars) or from uninfected controls (open bars) and analyzed by flow cytometry for the indicated markers. Data are expressed as mean fluorescence intensity relative to uninfected samples ± 1 s.d. (*p ≤ 0.05 uninfected versus P. chabaudi-infected). (d-g) Splenic DCs from uninfected (open bars) or P. chabaudi-infected (filled bars; 12 days post-infection) BALB/c mice were restimulated in vitro with LPS (1 μg/ml) for 18 h before analysis by flow cytometry for (d) MHC class II, (e) CD40, (f) CD80 and (g) CD86. Data are expressed as mean fluorescence intensity relative to uninfected, unstimulated samples ± 1 s.d. (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected for the same treatment).
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Figure 4: Modulation of DC activation in vivo during P. chabaudi infection. (a-c) Splenic CD11c+ DCs were isolated from P. chabaudi infected mice at various times (filled bars) or from uninfected controls (open bars) and analyzed by flow cytometry for the indicated markers. Data are expressed as mean fluorescence intensity relative to uninfected samples ± 1 s.d. (*p ≤ 0.05 uninfected versus P. chabaudi-infected). (d-g) Splenic DCs from uninfected (open bars) or P. chabaudi-infected (filled bars; 12 days post-infection) BALB/c mice were restimulated in vitro with LPS (1 μg/ml) for 18 h before analysis by flow cytometry for (d) MHC class II, (e) CD40, (f) CD80 and (g) CD86. Data are expressed as mean fluorescence intensity relative to uninfected, unstimulated samples ± 1 s.d. (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected for the same treatment).

Mentions: As our results suggested that malaria-infected erythrocytes might modulate the responsiveness of DCs in vitro, we next investigated the activation status of splenic DCs in vivo during a time-course of infection with P. chabaudi. DCs isolated from spleens of mice 4 days after infection showed a moderately activated phenotype, as demonstrated by increased expression of CD40 and CD80 (Figure 4a), confirming previous reports [45]. DCs isolated from infected animals 12 and 20 days after infection, however, showed a reduced level of activation, with lower levels of CD40, CD80, CD86 and MHC class II molecules on their surface compared with DCs from uninfected animals (Figure 4b,c). Whereas DCs from uninfected mice upregulated CD40, CD80 and CD86 following LPS stimulation (Figure 4d-g), DCs isolated from the spleens of P. chabaudi-infected mice remained refractory to in vitro LPS-induced maturation, with reduced levels of these molecules following stimulation. Thus it seems that, in vivo, DCs are activated soon after infection, and the level of activation on DCs is reduced following the peak of infection (days 12-20), and this cannot be abrogated by microbial stimulation ex vivo.


Suppression of adaptive immunity to heterologous antigens during Plasmodium infection through hemozoin-induced failure of dendritic cell function.

Millington OR, Di Lorenzo C, Phillips RS, Garside P, Brewer JM - J. Biol. (2006)

Modulation of DC activation in vivo during P. chabaudi infection. (a-c) Splenic CD11c+ DCs were isolated from P. chabaudi infected mice at various times (filled bars) or from uninfected controls (open bars) and analyzed by flow cytometry for the indicated markers. Data are expressed as mean fluorescence intensity relative to uninfected samples ± 1 s.d. (*p ≤ 0.05 uninfected versus P. chabaudi-infected). (d-g) Splenic DCs from uninfected (open bars) or P. chabaudi-infected (filled bars; 12 days post-infection) BALB/c mice were restimulated in vitro with LPS (1 μg/ml) for 18 h before analysis by flow cytometry for (d) MHC class II, (e) CD40, (f) CD80 and (g) CD86. Data are expressed as mean fluorescence intensity relative to uninfected, unstimulated samples ± 1 s.d. (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected for the same treatment).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC1561486&req=5

Figure 4: Modulation of DC activation in vivo during P. chabaudi infection. (a-c) Splenic CD11c+ DCs were isolated from P. chabaudi infected mice at various times (filled bars) or from uninfected controls (open bars) and analyzed by flow cytometry for the indicated markers. Data are expressed as mean fluorescence intensity relative to uninfected samples ± 1 s.d. (*p ≤ 0.05 uninfected versus P. chabaudi-infected). (d-g) Splenic DCs from uninfected (open bars) or P. chabaudi-infected (filled bars; 12 days post-infection) BALB/c mice were restimulated in vitro with LPS (1 μg/ml) for 18 h before analysis by flow cytometry for (d) MHC class II, (e) CD40, (f) CD80 and (g) CD86. Data are expressed as mean fluorescence intensity relative to uninfected, unstimulated samples ± 1 s.d. (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected for the same treatment).
Mentions: As our results suggested that malaria-infected erythrocytes might modulate the responsiveness of DCs in vitro, we next investigated the activation status of splenic DCs in vivo during a time-course of infection with P. chabaudi. DCs isolated from spleens of mice 4 days after infection showed a moderately activated phenotype, as demonstrated by increased expression of CD40 and CD80 (Figure 4a), confirming previous reports [45]. DCs isolated from infected animals 12 and 20 days after infection, however, showed a reduced level of activation, with lower levels of CD40, CD80, CD86 and MHC class II molecules on their surface compared with DCs from uninfected animals (Figure 4b,c). Whereas DCs from uninfected mice upregulated CD40, CD80 and CD86 following LPS stimulation (Figure 4d-g), DCs isolated from the spleens of P. chabaudi-infected mice remained refractory to in vitro LPS-induced maturation, with reduced levels of these molecules following stimulation. Thus it seems that, in vivo, DCs are activated soon after infection, and the level of activation on DCs is reduced following the peak of infection (days 12-20), and this cannot be abrogated by microbial stimulation ex vivo.

Bottom Line: This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice.Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens.Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell) membranes, reproduces the effect of intact infected red blood cells on DCs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, UK. owain.millington@strath.ac.uk

ABSTRACT

Background: Dendritic cells (DCs) are central to the initiation and regulation of the adaptive immune response during infection. Modulation of DC function may therefore allow evasion of the immune system by pathogens. Significant depression of the host's systemic immune response to both concurrent infections and heterologous vaccines has been observed during malaria infection, but the mechanisms underlying this immune hyporesponsiveness are controversial.

Results: Here, we demonstrate that the blood stages of malaria infection induce a failure of DC function in vitro and in vivo, causing suboptimal activation of T cells involved in heterologous immune responses. This effect on T-cell activation can be transferred to uninfected recipients by DCs isolated from infected mice. Significantly, T cells activated by these DCs subsequently lack effector function, as demonstrated by a failure to migrate to lymphoid-organ follicles, resulting in an absence of B-cell responses to heterologous antigens. Fractionation studies show that hemozoin, rather than infected erythrocyte (red blood cell) membranes, reproduces the effect of intact infected red blood cells on DCs. Furthermore, hemozoin-containing DCs could be identified in T-cell areas of the spleen in vivo.

Conclusion: Plasmodium infection inhibits the induction of adaptive immunity to heterologous antigens by modulating DC function, providing a potential explanation for epidemiological studies linking endemic malaria with secondary infections and reduced vaccine efficacy.

Show MeSH
Related in: MedlinePlus