Damage to the Blood-Brain Barrier during Experimental Cerebral Malaria Results from Synergistic Effects of CD8⁺T Cells with Different Specificities

Abstract

c CD8؉ T cells play a pathogenic role in the development of murine experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection in C57BL/6 mice. Only a limited number of CD8 ؉ epitopes have been described. Here, we report the identification of a new epitope from the bergheilysin protein recognized by PbA-specific CD8 ؉ T cells. Induction and functionality of these specific CD8 ؉ T cells were investigated in parallel with previously reported epitopes, using new tools such as tetramers and reporter cell lines that were developed for this study. We demonstrate that CD8 ؉ T cells of diverse specificities induced during PbA infection share many characteristics. They express cytolytic markers (gamma interferon [IFN-␥], granzyme B) and chemokine receptors (CXCR3, CCR5) and damage the blood-brain barrier in vivo. Our earlier finding that brain microvessels in mice infected with PbA, but not with non-ECM-causing strains, cross-presented a shared epitope was generalizable to these additional epitopes. Suppressing the induction of specific CD8؉ T cells through tolerization with a high-dose peptide injection was unable to confer protection against ECM, suggesting that CD8 ؉ T cells of other specificities participate in this process. The tools that we developed can be used to further investigate the heterogeneity of CD8 ؉ T cell responses that are involved in ECM. Malaria remains a global threat to humanity, claiming approximately 700,000 lives annually, with children under 5 years old making up the large majority of fatal cases (1). Cerebral malaria (CM) is the most devastating and deadly complication of Plasmodium falciparum infection, and mortality remains significant even with artesunate treatment (2). As ethical constraints limit the study of this complication in humans, mouse models in which mice susceptible to experimental cerebral malaria (ECM) display many characteristics that closely resemble the human pathology were developed (3-5). In ECM-susceptible C57BL/6J mice, infection with Plasmodium berghei ANKA (PbA), but not P. yoelii 17XNL (Py17XNL) or P. berghei NK65 (PbNK65), results in the accumulation of parasitized red blood cells (RBCs) in the brain microvasculature (6, 7) and other deep organs, leukocyte accumulation, blood-brain barrier (BBB) disruption, and hemorrhages (reviewed in reference 8).ECM mouse models have helped to uncover some of the mechanisms underlying the immunopathogenesis of this neuropathology. The T cell arm of the immune system plays an essential role in ECM development. CD4 ϩ T cell involvement is restricted mostly to the earlier phase of induction, while CD8 ϩ T cells are the principal pathogenic effectors since their depletion just before neurological symptoms manifest prevents ECM (9, 10). The inflammatory molecules IFN-␥, granzyme B, and perforin were also found to be essential, as mice deficient in these molecules do not succumb to this disease (11-13). By piecing together these and other findings in the literature, a model of ECM pathogenesis in which CD8 ϩ...

Splenic differentiation and emergence of CCR5+CXCL9+CXCL10+ monocyte-derived dendritic cells in the brain during cerebral malaria

“…As a consequence, expression of CXCL9 and CXCL10 by MO-DCs was not induced. These results are consistent with earlier studies showing that IFNγ produced by CD4 + T cells induce CXCL9 and CXCL10 expression, and promotes the recruitment of pathogenic CD8 + T cells to the brain of PbA-infected mice383946476162. Plasmodium DNA and RNA were also shown to activate other families of cytosolic innate immune receptors.…”

Host Resistance to Plasmodium-Induced Acute Immune Pathology Is Regulated by Interleukin-10 Receptor Signaling

“…While damage to brain vessels has implicated perforin and granzyme secretion in P. berghei ANKA-infected C57BL/6 mice (12–14), the roles of these molecules in BALB/c mice warrant further investigation. While it appears that the CTLA-4, PD-1/PD-L1, and IL-10-R pathways independently regulate host resistance to P.…”

Perforin Expression by CD8 T Cells Is Sufficient To Cause Fatal Brain Edema during Experimental Cerebral Malaria

“…Previous studies have indicated that the CD8 T cells recruited during ECM are specific to parasitic antigens (25,35,36). Therefore, this pathway appears to be initiated when CD8 T cells recognize major histocompatibility complex (MHC) class I molecules loaded with parasitic antigens and mediate BBB disruption downstream through perforin.…”