Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria |
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Authors: | Haque Ashraful Best Shannon E Unosson Klara Amante Fiona H de Labastida Fabian Anstey Nicholas M Karupiah Gunasegaran Smyth Mark J Heath William R Engwerda Christian R |
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Institution: | Immunology and Infection Laboratory, Queensland Institute of Medical Research, Herston, Brisbane, Queensland 4006, Australia. ashraful.haque@qimr.edu.au |
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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. |
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