title: Activated Brain Endothelial Cells Cross-Present Malaria Antigen.
abstract: 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.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Shanshan W
authors.initials: SW
authors.lastname: Howland
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chek Meng
authors.initials: CM
authors.lastname: Poh
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore; Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Laurent
authors.initials: L
authors.lastname: Rénia
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology*; D001921:Brain / Q000276:immunology* / Q000469:parasitology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D045142:Cross-Priming / Q000276:immunology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology*; D005455:Fluorescent Antibody Technique; D006801:Humans; D016779:Malaria, Cerebral / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000953:Antigens, Protozoan