CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions

Mayo Clinic Rochester, Rochester MN

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Abstract

ABSTRACT The most severe clinical complication of Plasmodium falciparum infection is cerebral malaria (CM) which has high morbidity despite treatment. Disruption of the blood-brain barrier (BBB), extensive edema, and brain swelling are associated with fatal human CM. Given the above observations in human CM, the mechanism of BBB disruption and vascular permeability needs to be defined. Plasmodium berghei ANKA (PbA) infection of mice is an established model of human CM. Considerable CNS pathology associated with PbA infection is driven by an acute CD8 T cell response which induces disruption of BBB tight junction proteins and CNS vascular permeability. Our laboratory developed an additional inducible model of CD8 T cell mediated BBB disruption which is initiated through administration of antigenic peptide. This Peptide Induced Fatal Syndrome (PIFS) model shares many similarities to lethal PbA infection in that CD8 T cells use perforin and engage brain vasculature to induce BBB disruption Importantly, we report that CD8 T resident memory (TRM) cells can induce BBB disruption, long after clearance of viral pathogen. We also demonstrate these CD8 TRM can be induced to mediate BBB disruption repeatedly, in multiple insults, at time points months apart. This discovery provides a unique opportunity to study the effects of CD8 TRM cells on brain vascular health and neuropathology in chronic phases of neurologic disease. Both PbA infection and the PIFS model employ a common pathway in which antigen-specific CD8 T cells engage endothelial cells of brain vasculature to promote BBB disruption. This was determined using our novel MHC class I conditional knockout mice generated by my research program. Our central hypothesis is CD8 T resident memory (TRM) cells directly engage brain vasculature in an MHC class I molecule restricted manner, initiating broad immune cell infiltration and BBB disruption. We will test this hypothesis through execution of the following aims: Specific Aim #1 – Identify the anatomical location of antigen-specific acute and memory CD8 T cell activation during onset of BBB disruption Specific Aim #2 – Determine the impact of T cell engagement of endothelial cell expressed MHC class I and MHC class II molecules on immune cell recruitment to brain parenchyma Specific Aim #3 – Define the neuropathological impact of repeated insult by CD8 TRM cell mediated BBB disruption The proposed work is innovative because it capitalizes on our unique transgenic mouse models, collaborations, novel imaging methodology, and core facilities available to our research program at Mayo Clinic. Our goal is to define mechanistically the contribution of inflammation to BBB disruption in neurologic disease using established models. Beyond the innovative methodology employed, the concept that antigen presentation by brain vasculature causes BBB disruption in acute and chronic phases of CNS disease has implications for the role of acute and memory CD8 T cells in complex human neurological conditions in general.