Tong Liu, Gang Wu, Cathrin L C Gudd, Francesca M Trovato, Thomas Barbera, Yan Liu, Evangelos Triantafyllou, Mark J W McPhail, Mark R Thursz, Wafa Khamri
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Potential cis-membrane ligands of CD52 were discovered via proximity labelling followed by proteomics. The function of CD52 on antigen-specific activation of CD4<sup>+</sup> T cells was examined using flow cytometry in CD52 CRISPR-Cas9 knockout primary T cells.</p><p><strong>Findings: </strong>CD52 expression was elevated in CD4<sup>+</sup> T cells in acute decompensation of cirrhosis, and this elevation was correlated with increased disease severity and mortality. Components of the T cell receptor complex including TCRβ, CD3γ and CD3ε were identified and validated as cis-membrane ligands of CD52. Knockout of CD52 promoted antigen-specific activation, proliferation, and pro-inflammatory cytokine secretion.</p><p><strong>Interpretation: </strong>Membrane bound CD52 demonstrated cis-interaction with the T cell receptor and served as a dynamic regulator of antigen-specific activation of CD4<sup>+</sup> T cells. 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引用次数: 0
摘要
背景：免疫功能障碍是肝硬化急性失代偿期患者感染率高的原因之一。CD52 是一种在淋巴细胞中显著表达的糖蛋白。CD52 的免疫调节功能可能与肝硬化患者的适应性免疫功能障碍有关。本研究旨在探讨肝硬化急性失代偿期患者血液中 CD4+ T 细胞上 CD52 的功能：方法：使用流式细胞术和转录组学研究了 49 例肝硬化患者外周血淋巴细胞中 CD52 的表达。通过近距离标记和蛋白质组学发现了 CD52 的潜在顺式膜配体。在 CD52 CRISPR-Cas9 基因敲除的原代 T 细胞中，使用流式细胞仪检测了 CD52 对 CD4+ T 细胞抗原特异性激活的功能：CD52在肝硬化急性失代偿期的CD4+T细胞中表达升高，这种升高与疾病严重程度和死亡率的增加相关。T细胞受体复合物（包括TCRβ、CD3γ和CD3ε）的成分被鉴定并验证为CD52的顺膜配体。敲除 CD52 可促进抗原特异性活化、增殖和促炎细胞因子分泌：膜结合 CD52 显示出与 T 细胞受体的顺式相互作用，是 CD4+ T 细胞抗原特异性活化的动态调节因子。肝硬化急性失代偿期外周 CD52 的上调阻碍了 MHC 对 T 细胞受体的识别，导致 T 细胞功能受损。要恢复肝硬化患者的T细胞功能并预防感染，就需要开发一种替代的抗CD52抗体：本研究得到了英国国家医学研究院帝国生物医学研究中心、转化医学和治疗研究所（P74713）、惠康基金会（218304/Z/19/Z）和医学研究委员会（MR/X009904/1和MR/R014019/1）的支持。
Cis-interaction between CD52 and T cell receptor complex interferes with CD4+ T cell activation in acute decompensation of cirrhosis.
Background: Immune dysfunction contributes to a high rate of infection in patients with acute decompensation of cirrhosis. CD52 is a glycoprotein prominently expressed in lymphocytes. Immune regulation by CD52 may be involved in adaptive immune dysfunction in cirrhosis. This study aimed to investigate the function of CD52 on CD4+ T cells on the blood of patients with acute decompensation of cirrhosis.
Methods: The expression of CD52 in the peripheral blood lymphocytes of 49 patients with cirrhosis was investigated using flow cytometry and transcriptomics. Potential cis-membrane ligands of CD52 were discovered via proximity labelling followed by proteomics. The function of CD52 on antigen-specific activation of CD4+ T cells was examined using flow cytometry in CD52 CRISPR-Cas9 knockout primary T cells.
Findings: CD52 expression was elevated in CD4+ T cells in acute decompensation of cirrhosis, and this elevation was correlated with increased disease severity and mortality. Components of the T cell receptor complex including TCRβ, CD3γ and CD3ε were identified and validated as cis-membrane ligands of CD52. Knockout of CD52 promoted antigen-specific activation, proliferation, and pro-inflammatory cytokine secretion.
Interpretation: Membrane bound CD52 demonstrated cis-interaction with the T cell receptor and served as a dynamic regulator of antigen-specific activation of CD4+ T cells. The upregulation of CD52 in the periphery of acute decompensation of cirrhosis hinders the recognition of the T cell receptor by MHC, contributing to impaired T cell function. The development of an alternative anti-CD52 antibody is required to restore T cell function and prevent infections in cirrhosis.
Funding: This study was supported by the NIHR Imperial Biomedical Research Centre, Institute for Translational Medicine and Therapeutics (P74713), Wellcome Trust (218304/Z/19/Z), and Medical Research Council (MR/X009904/1 and MR/R014019/1).
EBioMedicineBiochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
17.70
自引率
0.90%
发文量
579
审稿时长
5 weeks
期刊介绍：
eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.
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