Granzyme B expression by CD8⁺ T cells is required for the development of experimental cerebral malaria

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.