Dataset Information

CD8⁺ T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.

ABSTRACT:

Introduction

Cerebral 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.

Aims

To 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.

Results

The 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.

Conclusions

These 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.

SUBMITTER: Wang J

PROVIDER: S-EPMC10916431 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

CD8<sup>+</sup> T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.

Wang Jun J Zhu Qinghao Q Shen Yan Y Liang Jiao J Wang Yi Y Huang Yuxiao Y Tong Guodong G Wang Xu X Zhang Ningning N Yu Kangjie K Li Yinghui Y Zhao Ya Y

CNS neuroscience & therapeutics 20230912 3

<h4>Introduction</h4>Cerebral 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.<h4>Aims</h4>To explore cell composition and CD8<sup>+</sup> T cell infiltration, single-cell RNA sequencing (scRNA-seq) was performed on the brainstems o ...[more]

PMID: 37697956

Similar Datasets

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.

Project description:Cerebral malaria is a severe complication of human malaria and may lead to death of Plasmodium falciparum-infected individuals. Cerebral malaria is associated with sequestration of parasitized red blood cells within the cerebral microvasculature resulting in damage of the blood-brain barrier and brain pathology. Although CD8+ T cells have been implicated in the development of murine experimental cerebral malaria (ECM), several other studies have shown that CD8+ T cells confer protection against blood-stage infections. Since the role of host deubiquitinating enzymes (DUBs) in malaria is yet unknown, we investigated how the DUB cylindromatosis (CYLD), an important inhibitor of several cellular signaling pathways, influences the outcome of ECM. Upon infection with Plasmodium berghei ANKA (PbA) sporozoites or PbA-infected red blood cells, at least 90% of Cyld-/- mice survived the infection, whereas all congenic C57BL/6 mice displayed signatures of ECM, impaired parasite control, and disruption of the blood-brain barrier integrity. Cyld deficiency prevented brain pathology, including hemorrhagic lesions, enhanced activation of astrocytes and microglia, infiltration of CD8+ T cells, and apoptosis of endothelial cells. Furthermore, PbA-specific CD8+ T cell responses were augmented in the blood of Cyld-/- mice with increased production of interferon-γ and granzyme B and elevated activation of protein kinase C-θ and nuclear factor "kappa light-chain enhancer" of activated B cells. Importantly, accumulation of CD8+ T cells in the brain of Cyld-/- mice was significantly reduced compared to C57BL/6 mice. Bone marrow chimera experiments showed that the absence of ECM signatures in infected Cyld-/- mice could be attributed to hematopoietic and radioresistant parenchymal cells, most likely endothelial cells that did not undergo apoptosis. Together, we were able to show that host deubiqutinating enzymes play an important role in ECM and that CYLD promotes ECM supporting it as a potential therapeutic target for adjunct therapy to prevent cerebral complications of severe malaria.

Dataset Information

CD8⁺ T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.

Introduction

Aims

Results

Conclusions

Publications

CD8<sup>+</sup> T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

CD8+ T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.

Introduction

Aims

Results

Conclusions

Publications

CD8<sup>+</sup> T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

CD8⁺ T cell infiltration and proliferation in the brainstem during experimental cerebral malaria.