CD244 的上调促进了肺泡型包虫病患者和小鼠模型中 CD8 T 细胞衰竭。

Upregulation of CD244 promotes CD8 T cell exhaustion in patients with alveolar echinococcosis and a murine model.

机构信息

Department of Hepatobiliary and Echinococcosis Surgery, Digestive and Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China.

State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Xinjiang Medical University, Clinical Medicine Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, China.

出版信息

Parasit Vectors. 2024 Nov 23;17(1):483. doi: 10.1186/s13071-024-06573-2.

DOI:10.1186/s13071-024-06573-2

PMID:39578914

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11585139/

Abstract

BACKGROUND

In patients with alveolar echinococcosis (AE), CD8 T cells undergo functional exhaustion, which accelerates the malignant progression of AE. However, the role of inhibitory receptor CD244 in mediating CD8 T cell exhaustion remains elusive.

METHODS

CD244 expression on exhausted CD8 T cells in the close liver tissue (CLT) of AE patients was analyzed using single-cell RNA sequencing data. Immunohistochemistry and immunofluorescence were employed to detect CD244 expression. Flow cytometry was used to assess the impact of CD244 on differentiation and effector function of CD8 T cells in patients with AE, in vitro and in vivo models. Reactive oxygen species (ROS) and oxygen consumption rate (OCR) were measured to evaluate the influence of CD244 on mitochondrial function of CD8 T cells.

RESULTS

CD244CD8 T cells in the CLT of AE patients exhibit a more terminal differentiation phenotype, with reduced secretion of IFN-γ and TNF-α. In vitro studies revealed that CD8 T cells from CD244-deficient mice produced higher levels of IFN-γ, TNF-α and Granzyme B. In vivo studies revealed that CD244 deficiency enhanced the secretion capacity of IFN-γ and TNF-α by CD8 T cells, inhibiting the growth of metacestodes. Moreover, CD244 deficiency leads to a decrease in ROS levels in liver CD8 T cells, while significantly increasing their adenosine triphosphate (ATP)-linked oxygen consumption rate.

CONCLUSIONS

CD244 facilitates AE disease progression by mediating immune exhaustion in CD8 T cells.

摘要

背景

在细粒棘球蚴病（AE）患者中，CD8 T 细胞发生功能耗竭，加速 AE 的恶性进展。然而，抑制性受体 CD244 在介导 CD8 T 细胞耗竭中的作用仍不清楚。

方法

使用单细胞 RNA 测序数据分析 AE 患者肝内邻近组织（CLT）中耗竭的 CD8 T 细胞上 CD244 的表达。采用免疫组织化学和免疫荧光法检测 CD244 的表达。采用流式细胞术评估 CD244 对 AE 患者、体外和体内模型中 CD8 T 细胞分化和效应功能的影响。测量活性氧（ROS）和耗氧量（OCR）来评估 CD244 对 CD8 T 细胞线粒体功能的影响。

结果

AE 患者 CLT 中的 CD244CD8 T 细胞表现出更终末分化的表型，IFN-γ 和 TNF-α 的分泌减少。体外研究表明，CD244 缺陷型小鼠的 CD8 T 细胞产生更高水平的 IFN-γ、TNF-α 和 Granzyme B。体内研究表明，CD244 缺陷增强了 CD8 T 细胞 IFN-γ 和 TNF-α 的分泌能力，抑制了包虫生长。此外，CD244 缺陷导致肝 CD8 T 细胞中 ROS 水平降低，而显著增加其与三磷酸腺苷（ATP）相关的耗氧量。