Brain microvessel cross‐presentation is a hallmark of experimental cerebral malaria

Shanshan W Howland,Gijsbert M Grotenbreg,Chek Meng Poh,Florent Ginhoux,Carla Claser,Nilabh Shastri,Laurent Rénia,Benoit Malleret,Sin Yee Gun

doi:10.1002/emmm.201202273

Abstract

Cerebral malaria is a devastating complication of Plasmodium falciparum infection. Its pathogenesis is complex, involving both parasite- and immune-mediated events. CD8+ T cells play an effector role in murine experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA) infection. We have identified a highly immunogenic CD8 epitope in glideosome-associated protein 50 that is conserved across rodent malaria species. Epitope-specific CD8+ T cells are induced during PbA infection, migrating to the brain just before neurological signs manifest. They are functional, cytotoxic and can damage the blood–brain barrier in vivo. Such CD8+ T cells are also found in the brain during infection with parasite strains/species that do not induce neuropathology. We demonstrate here that PbA infection causes brain microvessels to cross-present parasite antigen, while non-ECM-causing parasites do not. Further, treatment with fast-acting anti-malarial drugs before the onset of ECM reduces parasite load and thus antigen presentation in the brain, preventing ECM death. Thus our data suggest that combined therapies targeting both the parasite and host antigen-presenting cells may improve the outcome of CM patients.

Highlights

Malaria remains one of the most important global health problems, affecting more than 200 million people and causing 655,000 deaths in 2010, most of them young children in Africa (World Health Organization, 2011)
T-cell receptor (TCR) sequencing of brain-sequestered CD8R T cells reveals an over-represented motif We sorted Vb8.1,2þ CD8þ T cells from the brains of Plasmodium berghei ANKA (PbA)-infected C57BL/6 mice exhibiting neurological signs and subjected these to single cell TCR sequencing
We developed two essential complimentary tools, a P. berghei antigen library in EL4 cells suited for class I MHC haplotype H-2b presentation and a reporter cell line, LR-BSL8.4a, that expresses a and b chains of the TCR derived from FACS-sorted, clonally expanded brainsequestered T cells

Summary

Introduction

Malaria remains one of the most important global health problems, affecting more than 200 million people and causing 655,000 deaths in 2010, most of them young children in Africa (World Health Organization, 2011). The role of CD4þ T cells in C57BL/6 mice is restricted to the earlier induction phase of ECM, as antibody depletion of these cells prevented ECM if performed 4 days post-infection (p.i.) but not 6 days p.i.; in contrast, CD8þ T-cell depletion at the later time point, just 1 day before the onset of neurological symptoms, completely abrogated ECM death ß 2013 The Authors.

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