Perivascular Arrest of CD8+ T Cells Is a Signature of Experimental Cerebral Malaria
Fig 10
Hypothetical model for the CD8+ T cell-dependent development of ECM.
(1) Pb ANKA infection leads to the upregulation of adhesion molecules and cross-presentation of parasite antigen by MHC-I on brain microvascular endothelial cells [85–87]. (2) This promotes transient interaction of Pb ANKA-pRBCs and rolling of activated CD8+ T cells on the luminal aspect of the brain microvessel endothelial cells. Beginning one day prior to signs of ECM, parasite-specific CD8+ T cells are recruited to the perivascular space, either via direct diapedesis across the endothelium, or migration via the highly permissive choroid plexus. In the perivascular space, parasite-specific CD8+ T cells form immune synapses with (3) parasite Ag-expressing APCs and (4) the basolateral membrane of cross-presenting endothelial cells. Perivascular APCs may acquire parasite antigen as a result of either transport of material across the vessel wall preceding generalized breakdown of the barrier or subsequent to breach of cerebral vascular integrity. (5) The interaction between CD8+ T cells and the basolateral membrane of endothelial cells leads to release of cytotoxic perforin and granzyme molecules in the perivascular space that down regulate intercellular tight junction proteins, damaging the vascular integrity and causing vasogenic edema. (6) Through an undefined mechanism, perivascular CD8+ T cells also communicate across the glia limitans to induce astrocyte and microglial activation. Activation of these cells further amplifies cerebral inflammation and dysfunction and provides a source of VEGF that concomitantly induces vascular leakage and resistance of endothelial cells to apoptosis. In non-ECM malarial infections, parasites do not accumulate in the brain, brain endothelial cells do not phagocytose or cross-present malaria antigen and perivascular CD8+ T cells fail to recognize their cognate antigen, restricting their pathogenic activity and preventing ECM development.