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Open Access Highly Accessed Research article

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

Owain R Millington13*, Caterina Di Lorenzo1, R Stephen Phillips2, Paul Garside13 and James M Brewer13

Author Affiliations

1 Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, UK

2 Division of Infection and Immunity, Joseph Black Building, University of Glasgow, Glasgow G12 8QQ, UK

3 Current address: Centre for Biophotonics, University of Strathclyde, Glasgow G4 0NR, UK

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Journal of Biology 2006, 5:5  doi:10.1186/jbiol34

Published: 12 April 2006

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.