[HTML][HTML] Activated brain endothelial cells cross-present malaria antigen

SW Howland, CM Poh, L Rénia - PLoS pathogens, 2015 - journals.plos.org
PLoS pathogens, 2015journals.plos.org
In the murine model of cerebral malaria caused by P. berghei ANKA (PbA), parasite-specific
CD8+ T cells directly induce pathology and have long been hypothesized to kill brain
endothelial cells that have internalized PbA antigen. We previously reported that brain
microvessel fragments from infected mice cross-present PbA epitopes, using reporter cells
transduced with epitope-specific T cell receptors. Here, we confirm that endothelial cells are
the population responsible for cross-presentation in vivo, not pericytes or microglia. PbA …
In the murine model of cerebral malaria caused by P. berghei ANKA (PbA), parasite-specific CD8+ T cells directly induce pathology and have long been hypothesized to kill brain endothelial cells that have internalized PbA antigen. We previously reported that brain microvessel fragments from infected mice cross-present PbA epitopes, using reporter cells transduced with epitope-specific T cell receptors. Here, we confirm that endothelial cells are the population responsible for cross-presentation in vivo, not pericytes or microglia. PbA antigen cross-presentation by primary brain endothelial cells in vitro confers susceptibility to killing by CD8+ T cells from infected mice. IFNγ stimulation is required for brain endothelial cross-presentation in vivo and in vitro, which occurs by a proteasome- and TAP-dependent mechanism. Parasite strains that do not induce cerebral malaria were phagocytosed and cross-presented less efficiently than PbA in vitro. The main source of antigen appears to be free merozoites, which were avidly phagocytosed. A human brain endothelial cell line also phagocytosed P. falciparum merozoites. Besides being the first demonstration of cross-presentation by brain endothelial cells, our results suggest that interfering with merozoite phagocytosis or antigen processing may be effective strategies for cerebral malaria intervention.
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