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


CONCLUSIONS
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.
Millington
Owain R
OR
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow G11 6NT, UK. owain.millington@strath.ac.uk
Di Lorenzo
Caterina
C
Phillips
R Stephen
RS
Garside
Paul
P
Brewer
James M
JM
D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000469:parasitology; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D004912:Erythrocytes / Q000276:immunology / Q000469:parasitology; D005260:Female; D006420:Hemeproteins / Q000276:immunology*; D007108:Immune Tolerance; D008288:Malaria / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010961:Plasmodium / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000469:parasitology
D000953:Antigens, Protozoan; D006420:Hemeproteins; C020753:hemozoin