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.

Type I interferons suppress CD4+ T‐cell‐dependent parasite control during blood‐stage Plasmodium infection

“…with control IgG, anti-CD4 or anti-CD8b mAbs, and parasite burdens assessed 2 days later. As reported previously [23,27], CD8b-depletion reduced parasite burdens (Fig. 1C).…”

“…Given recent data suggesting that CD8 1 T cells sustain high parasite burdens in this model [23,26,27], we investigated whether CD4 1 T cells provide help to the parasite-specific CD8 1 T-cell response, by using an established surrogate CD8 1 T-cell epitope-based system [28,29]. C57BL/6 mice receiving small numbers of CD45.1 1 ovalbumin-specific CD8 1 T cells from naïve OTI mice were infected with ovalbumin peptide (SIINFEKL)-expressing PbA (PbTG).…”

“…We hypothesized that regulatory mechanisms, which safe-guard against over-exuberant adaptive immune responses, hamper CD4 1 T-cell-dependent parasite control and have tested this hypothesis in an experimental model of cerebral malaria (ECM) caused by infection of C57BL/6 mice with Plasmodium berghei ANKA (PbA). CD8 1 T cells are known to mediate immune pathology in the brain in this model [18][19][20][21][22][23], but the roles of CD4 1 T cells have not been clearly defined. Although they contribute to disease pathogenesis [22,24,25], it is unclear whether CD4 1 T cells acquire any capacity to control parasites.…”

“…(Fig. 1A and B), although expression of the essential cytolytic molecule, granzyme B (GzmB) [23], was 40% lower in brain-recruited OTI cells from day 2 CD4-depleted mice compared with controls (GzmB MFI: 15587124 (anti-CD4 day 2 p.i.) versus 24217220 (control IgG) (n 5 5), po0.05 Mann-Whitney; data representative of two independent experiments).…”

The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis duringPlasmodium bergheiANKA Murine Malaria

“…In the Pb2A C57BL/6 model, CD4 + T cells mediate the induction phase of immunopathogenesis of ECM, whereas CD8 + T cells mediate the effector phase of disease (3) by perforin and granzyme-dependent apoptosis of brain endothelial cells (4)(5)(6). Nonetheless, compared with the role of CD8 + T cells during ECM, the immune mechanism of CD4 + T cell-mediated pathogenesis of ECM is less understood.…”