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

被引：2

作者：

Wang, Jun ^{[1
]}

Zhu, Qinghao ^{[1
]}

Shen, Yan ^{[1
]}

Liang, Jiao ^{[1
]}

Wang, Yi ^{[1
]}

Huang, Yuxiao ^{[1
]}

Tong, Guodong ^{[1
,2
]}

Wang, Xu ^{[3
]}

Zhang, Ningning ^{[3
]}

Yu, Kangjie ^{[4
]}

Li, Yinghui ^{[1
]}

Zhao, Ya ^{[1
]}

机构：

[1] Fourth Mil Med Univ, Dept Med Microbiol & Parasitol, Xian, Peoples R China

[2] Northwest Univ, Coll Life Sci, Xian, Peoples R China

[3] Fourth Mil Med Univ, Sch Basic Med Sci, Xian, Peoples R China

[4] Air Force Hosp Eastern Theater, Dept Pathol, Nanjing, Peoples R China

来源：

CNS NEUROSCIENCE & THERAPEUTICS | 2024年 / 30卷 / 03期

关键词：

astrocytes; brain-infiltrated CD8(+) T cell; brainstem; experimental cerebral malaria; PD-1/PD-L1; pathway; single-cell RNA sequencing; DEATH; LYMPHOCYTES; CHILDREN; MICE;

D O I：

10.1111/cns.14431

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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-? 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.

引用

页数：17