title: Perivascular Arrest of CD8+ T Cells Is a Signature of Experimental Cerebral Malaria.
abstract: There is significant evidence that brain-infiltrating CD8+ T cells play a central role in the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the mechanisms through which they mediate their pathogenic activity during malaria infection remain poorly understood. Utilizing intravital two-photon microscopy combined with detailed ex vivo flow cytometric analysis, we show that brain-infiltrating T cells accumulate within the perivascular spaces of brains of mice infected with both ECM-inducing (P. berghei ANKA) and non-inducing (P. berghei NK65) infections. However, perivascular T cells displayed an arrested behavior specifically during P. berghei ANKA infection, despite the brain-accumulating CD8+ T cells exhibiting comparable activation phenotypes during both infections. We observed T cells forming long-term cognate interactions with CX3CR1-bearing antigen presenting cells within the brains during P. berghei ANKA infection, but abrogation of this interaction by targeted depletion of the APC cells failed to prevent ECM development. Pathogenic CD8+ T cells were found to colocalize with rare apoptotic cells expressing CD31, a marker of endothelial cells, within the brain during ECM. However, cellular apoptosis was a rare event and did not result in loss of cerebral vasculature or correspond with the extensive disruption to its integrity observed during ECM. In summary, our data show that the arrest of T cells in the perivascular compartments of the brain is a unique signature of ECM-inducing malaria infection and implies an important role for this event in the development of the ECM-syndrome.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Tovah N
authors.initials: TN
authors.lastname: Shaw
authors.affiliation: Molecular Pathogenesis Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York, New York, United States of America.|Department of Pediatric Research, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Stewart-Hutchinson
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Strangward
authors.affiliation: Immunology and Inflammation Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York, New York, United States of America.
authors.forename: Durga B
authors.initials: DB
authors.lastname: Dandamudi
authors.affiliation: Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coles
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Ana
authors.initials: A
authors.lastname: Villegas-Mendez
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Julio
authors.initials: J
authors.lastname: Gallego-Delgado
authors.affiliation: Department of Molecular Cell Biology, VU Medical Center, Amsterdam, The Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: The Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Egor
authors.initials: E
authors.lastname: Zindy
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Ana
authors.initials: A
authors.lastname: Rodriguez
authors.affiliation: Centre for Immunobiology, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: James M
authors.initials: JM
authors.lastname: Brewer
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Couper
authors.affiliation: Molecular Pathogenesis Program, Helen L. and Martin S. Kimmel Center for Biology and Medicine, Skirball Institute of Biomolecular Medicine, New York, New York, United States of America.|The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics and Musculoskeletal Sciences, The University of Oxford, Headington, United Kingdom.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Dustin
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000469:parasitology; D004195:Disease Models, Animal; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D016778:Malaria, Falciparum / Q000382:microbiology*; D008810:Mice, Inbred C57BL; D018512:Parasitemia / Q000276:immunology*; D010962:Plasmodium berghei / Q000276:immunology*