Dataset Information

Comparison of CD8+ T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria.

ABSTRACT: CD8+ T cells have been shown to play a critical role in the pathogenesis of experimental cerebral malaria (ECM) in mice, but their role in development of human cerebral malaria (HCM) remains unclear. Thus, in this study we have provided the first direct contrast of the accumulation of CD8+ T cells in the brain during HCM and ECM. HCM cases were from children who died of Plasmodium falciparum cerebral malaria at Queen Elizabeth Central Hospital (Malawi) between 2003 and 2010. ECM was induced by infecting C57BL/6J mice with P. berghei ANKA. We demonstrate similarities in the intracerebral CD8+ T cell responses in ECM and HCM, in particular an apparent shared choroid plexus-meningeal route of CD8+ T cell accumulation in the brain. Nevertheless, we also reveal some potentially important differences in compartmentalization of CD8+ T cells within the cerebrovascular bed in HCM and ECM.

SUBMITTER: Barrera V

PROVIDER: S-EPMC6668485 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Comparison of CD8+ T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria.

Barrera Valentina V Haley Michael J MJ Strangward Patrick P Attree Elizabeth E Kamiza Steve S Seydel Karl B KB Taylor Terrie E TE Milner Danny A DA Craig Alister G AG Couper Kevin N KN

Frontiers in immunology 20190724

CD8+ T cells have been shown to play a critical role in the pathogenesis of experimental cerebral malaria (ECM) in mice, but their role in development of human cerebral malaria (HCM) remains unclear. Thus, in this study we have provided the first direct contrast of the accumulation of CD8+ T cells in the brain during HCM and ECM. HCM cases were from children who died of Plasmodium falciparum cerebral malaria at Queen Elizabeth Central Hospital (Malawi) between 2003 a ...[more]

PMID: 31396236

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Project description:IntroductionCerebral malaria (CM) is a lethal neuroinflammatory disease caused by Plasmodium infection. Immune cells and brain parenchyma cells contribute to the pathogenesis of CM. However, a systematic examination of the changes that occur in the brain parenchyma region during CM at the single-cell resolution is still poorly studied.AimsTo explore cell composition and CD8+ T cell infiltration, single-cell RNA sequencing (scRNA-seq) was performed on the brainstems of healthy and experimental cerebral malaria (ECM) mice. Then CD8+ T cell infiltration was confirmed by flow cytometry and immunofluorescence assays. Subsequently, the characteristics of the brain-infiltrated CD8+ T cells were analyzed. Finally, the interactions between parenchyma cells and brain-infiltrated CD8+ T cells were studied with an astrocytes-CD8+ T cell cocultured model.ResultsThe brainstem is the most severely damaged site during ECM. ScRNA-seq revealed a large number of CD8+ T cells infiltrating into the brainstem in ECM mice. Brain-infiltrated CD8+ T cells were highly activated according to scRNA-seq, immunofluorescence, and flow cytometry assays. Further analysis found a subset of ki-67+ CD8+ T cells that have a higher transcriptional level of genes related to T cell function, activation, and proliferation, suggesting that they were exposed to specific antigens presented by brain parenchyma cells. Brain-infiltrated CD8+ T cells were the only prominent source of IFN-γ in this single-cell analysis. Astrocytes, which have a high interferon response, act as cross-presenting cells to recruit and re-activate brain-infiltrated CD8+ T cells. We also found that brain-infiltrated CD8+ T cells were highly expressed immune checkpoint molecule PD-1, while parenchyma cells showed up-regulation of PD-L1 after infection.ConclusionsThese findings reveal a novel interaction between brain-infiltrated CD8+ T cells and parenchyma cells in the ECM brainstem, suggesting that the PD-1/PD-L1 signal pathway is a promising adjunctive therapeutic strategy for ECM targeting over-activated CD8+ T cells.

Project description:Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that results in thousands of deaths each year, mostly in African children. The in vivo mechanisms underlying this fatal condition are not entirely understood. Using the animal model of experimental cerebral malaria (ECM), we sought mechanistic insights into the pathogenesis of CM. Fatal disease was associated with alterations in tight junction proteins, vascular breakdown in the meninges / parenchyma, edema, and ultimately neuronal cell death in the brainstem, which is consistent with cerebral herniation as a cause of death. At the peak of ECM, we revealed using intravital two-photon microscopy that myelomonocytic cells and parasite-specific CD8+ T cells associated primarily with the luminal surface of CNS blood vessels. Myelomonocytic cells participated in the removal of parasitized red blood cells (pRBCs) from cerebral blood vessels, but were not required for the disease. Interestingly, the majority of disease-inducing parasite-specific CD8+ T cells interacted with the lumen of brain vascular endothelial cells (ECs), where they were observed surveying, dividing, and arresting in a cognate peptide-MHC I dependent manner. These activities were critically dependent on IFN-γ, which was responsible for activating cerebrovascular ECs to upregulate adhesion and antigen-presenting molecules. Importantly, parasite-specific CD8+ T cell interactions with cerebral vessels were impaired in chimeric mice rendered unable to present EC antigens on MHC I, and these mice were in turn resistant to fatal brainstem pathology. Moreover, anti-adhesion molecule (LFA-1 / VLA-4) therapy prevented fatal disease by rapidly displacing luminal CD8+ T cells from cerebrovascular ECs without affecting extravascular T cells. These in vivo data demonstrate that parasite-specific CD8+ T cell-induced fatal vascular breakdown and subsequent neuronal death during ECM is associated with luminal, antigen-dependent interactions with cerebrovasculature.

Dataset Information

Comparison of CD8+ T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria.

Publications

Comparison of CD8<sup>+</sup> T Cell Accumulation in the Brain During Human and Murine Cerebral Malaria.

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