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.
Haque, A., Best, S., Unosson, K., Amante, F., de Labastida Rivera, F., Anstey, N., Karupiah, G., Smyth, M., Heath, W., & Engwerda, C. R. (2011). Granzyme B expression by CD8 + T cells is required for the development of experimental cerebral malaria. Journal of Immunology, 186(11), 6148-6156. https://doi.org/10.4049/jimmunol.1003955