Antigen presentation by discrete class I molecules on brain endothelium dynamically regulates T-cell mediated neuropathology in experimental cerebral malaria

Abstract

AbstractCD8 T cell engagement of brain vasculature is a putative mechanism of neuropathology in human cerebral malaria. To define contributions of brain endothelial cell MHC class I antigen-presentation to CD8 T cells in establishing this pathology, we developed novel H-2KbLoxP and H-2DbLoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules on brain endothelium. Using thePlasmodium bergheiANKA model of experimental cerebral malaria (ECM), we observe that H-2Kband H-2Dbregulate distinct patterns of disease onset, CD8 T cell infiltration, targeted cell death, and regional blood-brain barrier (BBB) disruption. Strikingly, ablation of H-2Kbor H-2Dbfrom brain endothelial cells resulted in reduced CD8 T cell activation, attenuated T cell interaction with brain vasculature, lessened targeted cell death, preserved BBB integrity, and prevented ECM and the death of the animal. These data demonstrate that interactions of CD8 T cells with discrete MHC class I molecules on brain endothelium regulate development of ECM neuropathology. Therefore, targeting MHC class I interactions therapeutically may hold potential for treatment of cases of severe malaria.