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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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Deposition of HZ in DCs suppresses maturation. (a) HZ content in bone-marrow-derived DCs (In vitro), purified DCs (Ex vivo) and spleen sections (In vivo) was visualized by light microscopy (top images) or by false-coloring malaria pigment viewed in bright-field image (red) and superimposing over the fluorescent CD11c image (green). (b) CD11c+ DCs were analyzed for size and granularity by flow cytometry 12 days post-infection with P. chabaudi or in uninfected controls. Data are expressed as the mean forward scatter or side scatter of triplicate samples ± 1 s.d. (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected). (c-e) 2 × 106 DCs were cultured with 1 μM, 5 μM, 10 μM and 20 μM of HZ. After 24 h, the level of expression of (c) MHC class II, (d) CD40 and (e) CD86 on CD11c+ cells was determined by FACS analysis. (f-h) After 24 h culture with HZ, 1 μg/ml LPS was added to DCs and the levels of (f) MHC class II, (g) CD40, and (h) CD86 were analyzed 18 h later by FACS. All results are shown as the mean fluorescence intensity on CD11c+ DCs in triplicate samples ± s.e. (*p ≤ 0.05 HZ versus LPS).
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Figure 6: Deposition of HZ in DCs suppresses maturation. (a) HZ content in bone-marrow-derived DCs (In vitro), purified DCs (Ex vivo) and spleen sections (In vivo) was visualized by light microscopy (top images) or by false-coloring malaria pigment viewed in bright-field image (red) and superimposing over the fluorescent CD11c image (green). (b) CD11c+ DCs were analyzed for size and granularity by flow cytometry 12 days post-infection with P. chabaudi or in uninfected controls. Data are expressed as the mean forward scatter or side scatter of triplicate samples ± 1 s.d. (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected). (c-e) 2 × 106 DCs were cultured with 1 μM, 5 μM, 10 μM and 20 μM of HZ. After 24 h, the level of expression of (c) MHC class II, (d) CD40 and (e) CD86 on CD11c+ cells was determined by FACS analysis. (f-h) After 24 h culture with HZ, 1 μg/ml LPS was added to DCs and the levels of (f) MHC class II, (g) CD40, and (h) CD86 were analyzed 18 h later by FACS. All results are shown as the mean fluorescence intensity on CD11c+ DCs in triplicate samples ± s.e. (*p ≤ 0.05 HZ versus LPS).

Mentions: Having established that parasite proteins expressed on the erythrocyte cell membrane are not responsible for the modulation of LPS-induced maturation of DCs in vitro, we focused our attention on HZ, a by-product of hemoglobin digestion. We observed that bone-marrow-derived DCs cultured in vitro with infected erythrocytes accumulated intracellular malarial pigment (Figure 6a). Flow cytometric analysis of splenic DCs, identified by CD11c expression, also demonstrated an increase in the size and granularity of DCs during infection (Figure 6b), and DCs isolated ex vivo as well as DCs in spleen sections showed conspicuous HZ deposition (Figure 6a).


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)

Deposition of HZ in DCs suppresses maturation. (a) HZ content in bone-marrow-derived DCs (In vitro), purified DCs (Ex vivo) and spleen sections (In vivo) was visualized by light microscopy (top images) or by false-coloring malaria pigment viewed in bright-field image (red) and superimposing over the fluorescent CD11c image (green). (b) CD11c+ DCs were analyzed for size and granularity by flow cytometry 12 days post-infection with P. chabaudi or in uninfected controls. Data are expressed as the mean forward scatter or side scatter of triplicate samples ± 1 s.d. (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected). (c-e) 2 × 106 DCs were cultured with 1 μM, 5 μM, 10 μM and 20 μM of HZ. After 24 h, the level of expression of (c) MHC class II, (d) CD40 and (e) CD86 on CD11c+ cells was determined by FACS analysis. (f-h) After 24 h culture with HZ, 1 μg/ml LPS was added to DCs and the levels of (f) MHC class II, (g) CD40, and (h) CD86 were analyzed 18 h later by FACS. All results are shown as the mean fluorescence intensity on CD11c+ DCs in triplicate samples ± s.e. (*p ≤ 0.05 HZ versus LPS).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Deposition of HZ in DCs suppresses maturation. (a) HZ content in bone-marrow-derived DCs (In vitro), purified DCs (Ex vivo) and spleen sections (In vivo) was visualized by light microscopy (top images) or by false-coloring malaria pigment viewed in bright-field image (red) and superimposing over the fluorescent CD11c image (green). (b) CD11c+ DCs were analyzed for size and granularity by flow cytometry 12 days post-infection with P. chabaudi or in uninfected controls. Data are expressed as the mean forward scatter or side scatter of triplicate samples ± 1 s.d. (*p ≤ 0.05, #p ≤ 0.005 uninfected versus P. chabaudi-infected). (c-e) 2 × 106 DCs were cultured with 1 μM, 5 μM, 10 μM and 20 μM of HZ. After 24 h, the level of expression of (c) MHC class II, (d) CD40 and (e) CD86 on CD11c+ cells was determined by FACS analysis. (f-h) After 24 h culture with HZ, 1 μg/ml LPS was added to DCs and the levels of (f) MHC class II, (g) CD40, and (h) CD86 were analyzed 18 h later by FACS. All results are shown as the mean fluorescence intensity on CD11c+ DCs in triplicate samples ± s.e. (*p ≤ 0.05 HZ versus LPS).
Mentions: Having established that parasite proteins expressed on the erythrocyte cell membrane are not responsible for the modulation of LPS-induced maturation of DCs in vitro, we focused our attention on HZ, a by-product of hemoglobin digestion. We observed that bone-marrow-derived DCs cultured in vitro with infected erythrocytes accumulated intracellular malarial pigment (Figure 6a). Flow cytometric analysis of splenic DCs, identified by CD11c expression, also demonstrated an increase in the size and granularity of DCs during infection (Figure 6b), and DCs isolated ex vivo as well as DCs in spleen sections showed conspicuous HZ deposition (Figure 6a).

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