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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.

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.

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Related in: MedlinePlus

P. chabaudi-infected erythrocytes inhibit the ability of DCs to efficiently activate naive T cells in vitro. DCs (2 × 105) were treated with infected (pRBC) or uninfected (RBC) erythrocytes for 24 h. DCs were then loaded with 5 mg/ml of OVA for 6 h. 5 × 105 untreated (Control), RBC or pRBC-treated DCs and 5 × 105 DO11.10 lymph node cells were then co-cultured. (a) CD69 expression assessed on DO11.10 T cells 24 h later by FACS analysis. Results are expressed as the percentage of antigen-specific cells expressing CD69 in cultures stimulated by OVA-pulsed DCs (filled bars) or by DCs only (open bars). Results show the mean of triplicate samples ± s.e. (b) [3H]thymidine was added for the last 18 h of culture; c.p.m., counts per min. Results show mean proliferation of OVA-specific T cells after incubation with DCs treated with uninfected RBCs (open circles) or pRBCs (filled circles) in triplicate samples ± s.e. The concentrations of (c) IL-2, (d) IL-5 (e) IL-10, and (f) IFN-γ secreted by OVA-specific T cells after incubation with DCs treated with uninfected RBCs (open circles) or pRBCs (filled circles) were measured in supernatants harvested after 24, 48, and 72 h of culture.
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Figure 7: P. chabaudi-infected erythrocytes inhibit the ability of DCs to efficiently activate naive T cells in vitro. DCs (2 × 105) were treated with infected (pRBC) or uninfected (RBC) erythrocytes for 24 h. DCs were then loaded with 5 mg/ml of OVA for 6 h. 5 × 105 untreated (Control), RBC or pRBC-treated DCs and 5 × 105 DO11.10 lymph node cells were then co-cultured. (a) CD69 expression assessed on DO11.10 T cells 24 h later by FACS analysis. Results are expressed as the percentage of antigen-specific cells expressing CD69 in cultures stimulated by OVA-pulsed DCs (filled bars) or by DCs only (open bars). Results show the mean of triplicate samples ± s.e. (b) [3H]thymidine was added for the last 18 h of culture; c.p.m., counts per min. Results show mean proliferation of OVA-specific T cells after incubation with DCs treated with uninfected RBCs (open circles) or pRBCs (filled circles) in triplicate samples ± s.e. The concentrations of (c) IL-2, (d) IL-5 (e) IL-10, and (f) IFN-γ secreted by OVA-specific T cells after incubation with DCs treated with uninfected RBCs (open circles) or pRBCs (filled circles) were measured in supernatants harvested after 24, 48, and 72 h of culture.

Mentions: The above experiments clearly implicated HZ-mediated suppression of DC function in the failure of antibody production and in the delayed acquisition of protective immunity seen during malaria infection in vivo. To examine the functional consequences of malaria on DC function directly, we examined the ability of affected DCs to activate naive, OVA-specific T-cell receptor-transgenic T cells. These cells allow monitoring of the antigen-specific CD4+ T-cell response as their antigen specificity is known and they can be tracked using a clonotypic antibody directed against their T-cell receptor. One of the earliest cell-surface antigens expressed by T cells following activation is CD69, which is detectable within an hour of ligation of the T-cell receptor complex [48]. Interestingly, there was no significant difference in the percentage of OVA-specific T cells expressing CD69 between RBC-treated and pRBC-treated groups (Figure 7a), showing that T cells interacting with modulated DCs are equally activated.


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)

P. chabaudi-infected erythrocytes inhibit the ability of DCs to efficiently activate naive T cells in vitro. DCs (2 × 105) were treated with infected (pRBC) or uninfected (RBC) erythrocytes for 24 h. DCs were then loaded with 5 mg/ml of OVA for 6 h. 5 × 105 untreated (Control), RBC or pRBC-treated DCs and 5 × 105 DO11.10 lymph node cells were then co-cultured. (a) CD69 expression assessed on DO11.10 T cells 24 h later by FACS analysis. Results are expressed as the percentage of antigen-specific cells expressing CD69 in cultures stimulated by OVA-pulsed DCs (filled bars) or by DCs only (open bars). Results show the mean of triplicate samples ± s.e. (b) [3H]thymidine was added for the last 18 h of culture; c.p.m., counts per min. Results show mean proliferation of OVA-specific T cells after incubation with DCs treated with uninfected RBCs (open circles) or pRBCs (filled circles) in triplicate samples ± s.e. The concentrations of (c) IL-2, (d) IL-5 (e) IL-10, and (f) IFN-γ secreted by OVA-specific T cells after incubation with DCs treated with uninfected RBCs (open circles) or pRBCs (filled circles) were measured in supernatants harvested after 24, 48, and 72 h of culture.
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Related In: Results  -  Collection

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Figure 7: P. chabaudi-infected erythrocytes inhibit the ability of DCs to efficiently activate naive T cells in vitro. DCs (2 × 105) were treated with infected (pRBC) or uninfected (RBC) erythrocytes for 24 h. DCs were then loaded with 5 mg/ml of OVA for 6 h. 5 × 105 untreated (Control), RBC or pRBC-treated DCs and 5 × 105 DO11.10 lymph node cells were then co-cultured. (a) CD69 expression assessed on DO11.10 T cells 24 h later by FACS analysis. Results are expressed as the percentage of antigen-specific cells expressing CD69 in cultures stimulated by OVA-pulsed DCs (filled bars) or by DCs only (open bars). Results show the mean of triplicate samples ± s.e. (b) [3H]thymidine was added for the last 18 h of culture; c.p.m., counts per min. Results show mean proliferation of OVA-specific T cells after incubation with DCs treated with uninfected RBCs (open circles) or pRBCs (filled circles) in triplicate samples ± s.e. The concentrations of (c) IL-2, (d) IL-5 (e) IL-10, and (f) IFN-γ secreted by OVA-specific T cells after incubation with DCs treated with uninfected RBCs (open circles) or pRBCs (filled circles) were measured in supernatants harvested after 24, 48, and 72 h of culture.
Mentions: The above experiments clearly implicated HZ-mediated suppression of DC function in the failure of antibody production and in the delayed acquisition of protective immunity seen during malaria infection in vivo. To examine the functional consequences of malaria on DC function directly, we examined the ability of affected DCs to activate naive, OVA-specific T-cell receptor-transgenic T cells. These cells allow monitoring of the antigen-specific CD4+ T-cell response as their antigen specificity is known and they can be tracked using a clonotypic antibody directed against their T-cell receptor. One of the earliest cell-surface antigens expressed by T cells following activation is CD69, which is detectable within an hour of ligation of the T-cell receptor complex [48]. Interestingly, there was no significant difference in the percentage of OVA-specific T cells expressing CD69 between RBC-treated and pRBC-treated groups (Figure 7a), showing that T cells interacting with modulated DCs are equally activated.

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