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

IF 3 2区医学 Q1 PARASITOLOGY Parasites & Vectors Pub Date : 2024-11-23 DOI:10.1186/s13071-024-06573-2

Maolin Wang, Bingqing Deng, Tiemin Jiang, Adilai Duolikun, Yinshi Li, Abidan Ainiwaer, Xuejiao Kang, Xuran Zheng, Zibigu Rousu, Qian Yu, Jing Li, Hui Wang, Chuanshan Zhang, Tuerganaili Aji, Yingmei Shao

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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: CD244⁺CD8⁺ 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.

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CD244 的上调会促进肺泡棘球蚴病患者和小鼠模型中 CD8+ T 细胞的衰竭。

背景：在肺泡棘球蚴病（AE）患者中，CD8+ T细胞功能衰竭，这加速了AE的恶性进展。然而，抑制性受体 CD244 在介导 CD8+ T 细胞衰竭中的作用仍不明确：方法：利用单细胞 RNA 测序数据分析了 AE 患者近端肝组织（CLT）中衰竭的 CD8+ T 细胞上 CD244 的表达。免疫组化和免疫荧光被用来检测CD244的表达。流式细胞术用于评估 CD244 在体外和体内模型中对 AE 患者 CD8+ T 细胞分化和效应功能的影响。测量了活性氧（ROS）和耗氧量（OCR），以评估CD244对CD8+ T细胞线粒体功能的影响：结果：AE患者CLT中的CD244+CD8+ T细胞表现出更多的终末分化表型，IFN-γ和TNF-α分泌减少。体外研究发现，CD244缺陷小鼠的CD8+T细胞能产生更高水平的IFN-γ、TNF-α和颗粒酶B。体内研究发现，CD244缺陷增强了CD8+T细胞分泌IFN-γ和TNF-α的能力，从而抑制了 metacestodes的生长。此外，CD244缺乏会导致肝脏CD8+ T细胞中的ROS水平下降，同时显著增加其与三磷酸腺苷（ATP）相关的耗氧率：结论：CD244通过介导CD8+ T细胞的免疫耗竭而促进AE疾病的进展。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Parasites & Vectors 医学-寄生虫学

CiteScore

6.30

自引率

9.40%

发文量

433

审稿时长

1.4 months

期刊介绍： Parasites & Vectors is an open access, peer-reviewed online journal dealing with the biology of parasites, parasitic diseases, intermediate hosts, vectors and vector-borne pathogens. Manuscripts published in this journal will be available to all worldwide, with no barriers to access, immediately following acceptance. However, authors retain the copyright of their material and may use it, or distribute it, as they wish. Manuscripts on all aspects of the basic and applied biology of parasites, intermediate hosts, vectors and vector-borne pathogens will be considered. In addition to the traditional and well-established areas of science in these fields, we also aim to provide a vehicle for publication of the rapidly developing resources and technology in parasite, intermediate host and vector genomics and their impacts on biological research. We are able to publish large datasets and extensive results, frequently associated with genomic and post-genomic technologies, which are not readily accommodated in traditional journals. Manuscripts addressing broader issues, for example economics, social sciences and global climate change in relation to parasites, vectors and disease control, are also welcomed.