TY - JOUR
T1 - Granzyme B expression by CD8 + T cells is required for the development of experimental cerebral malaria
AU - Haque, Ashraful
AU - Best, Shannon
AU - Unosson, Klara
AU - Amante, Fiona
AU - de Labastida, Fabian
AU - Anstey, Nicholas
AU - Karupiah, Gunasegaran
AU - Smyth, Mark
AU - Heath, William
AU - Engwerda, Christian
PY - 2011/6/1
Y1 - 2011/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79958031319&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1003955
DO - 10.4049/jimmunol.1003955
M3 - Article
SN - 0022-1767
VL - 186
SP - 6148
EP - 6156
JO - Journal of Immunology
JF - Journal of Immunology
IS - 11
ER -