title: Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria.
abstract: Parasite burden predicts disease severity in malaria and risk of death in cerebral malaria patients. In murine experimental cerebral malaria (ECM), parasite burden and CD8(+) T cells promote disease by mechanisms that are not fully understood. We found that the majority of brain-recruited CD8(+) T cells expressed granzyme B (GzmB). Furthermore, gzmB(-/-) mice harbored reduced parasite numbers in the brain as a consequence of enhanced antiparasitic CD4(+) T cell responses and were protected from ECM. We showed in these ECM-resistant mice that adoptively transferred, Ag-specific CD8(+) T cells migrated to the brain, but did not induce ECM until a critical Ag threshold was reached. ECM induction was exquisitely dependent on Ag-specific CD8(+) T cell-derived perforin and GzmB, but not IFN-γ. In wild-type mice, full activation of brain-recruited CD8(+) T cells also depended on a critical number of parasites in this tissue, which in turn, was sustained by these tissue-recruited cells. Thus, an interdependent relationship between parasite burden and CD8(+) T cells dictates the onset of perforin/GzmB-mediated ECM.
authors.affiliation: Immunology and Infection Laboratory, Queensland Institute of Medical Research, Herston, Brisbane, Queensland 4006, Australia. ashraful.haque@qimr.edu.au
authors.forename: Ashraful
authors.initials: A
authors.lastname: Haque
authors.forename: Shannon E
authors.initials: SE
authors.lastname: Best
authors.forename: Klara
authors.initials: K
authors.lastname: Unosson
authors.forename: Fiona H
authors.initials: FH
authors.lastname: Amante
authors.forename: Fabian
authors.initials: F
authors.lastname: de Labastida
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Anstey
authors.forename: Gunasegaran
authors.initials: G
authors.lastname: Karupiah
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002465:Cell Movement / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000235:genetics / Q000276:immunology*; D006790:Host-Parasite Interactions / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D016788:Plasmodium chabaudi / Q000276:immunology / Q000502:physiology; D010967:Plasmodium yoelii / Q000276:immunology / Q000502:physiology
chemical_list: D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes