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慢性乙肝患者T细胞和自然杀伤细胞上免疫检查点分子的肝内表达差异。

Differences in the intrahepatic expression of immune checkpoint molecules on T cells and natural killer cells in chronic HBV patients.

作者信息

Dumolard Lucile, Hilleret Marie-Noelle, Costentin Charlotte, Mercey-Ressejac Marion, Sturm Nathalie, Gerster Theophile, Decaens Thomas, Jouvin-Marche Evelyne, Marche Patrice N, Macek Jilkova Zuzana

机构信息

Univ. Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, Grenoble, France.

Service d'hépato-gastroentérologie, Pôle Digidune, CHU Grenoble Alpes, La Tronche, France.

出版信息

Front Immunol. 2025 Jan 15;15:1489770. doi: 10.3389/fimmu.2024.1489770. eCollection 2024.

DOI:10.3389/fimmu.2024.1489770
PMID:39882238
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11774737/
Abstract

BACKGROUND

Patients with chronic hepatitis B virus (HBV) infection are characterized by impaired immune response that fails to eliminate HBV. Immune checkpoint molecules (ICMs) control the amplitude of the activation and function of immune cells, which makes them the key regulators of immune response.

METHODS

We performed a multiparametric flow cytometry analysis of ICMs and determined their expression on intrahepatic lymphocyte subsets in untreated and treated patients with HBV in comparison with non-pathological liver tissue.

RESULTS

The liver of untreated HBV patients exhibited a high accumulation of PD-1CD8 T cells, while the frequencies of 4-1BB T cells, 4-1BB natural killer (NK) cells, and TIM-3CD8 T cells were the highest in the chronic hepatitis phase. Our findings showed that the HBeAg status is linked to a distinct immune phenotype of intrahepatic CD8 T cells and NK cells characterized by high expression of ICMs, particularly 4-1BB. Importantly, antiviral treatment partially restored the normal expression of ICMs. Finally, we described important differences in ICM expression between intrahepatic and circulating NK cells in HBV patients.

CONCLUSIONS

Our study shows clear differences in the intrahepatic expression of ICMs on NK cells and T cells in chronic HBV patients depending on their clinical stage.

摘要

背景

慢性乙型肝炎病毒（HBV）感染患者的特征是免疫反应受损，无法清除HBV。免疫检查点分子（ICM）控制免疫细胞激活和功能的幅度，这使其成为免疫反应的关键调节因子。

方法

我们对ICM进行了多参数流式细胞术分析，并与非病理性肝组织相比，确定了它们在未经治疗和接受治疗的HBV患者肝内淋巴细胞亚群上的表达。

结果

未经治疗的HBV患者肝脏中PD-1⁺CD8⁺ T细胞高度聚集，而4-1BB⁺ T细胞、4-1BB⁺自然杀伤（NK）细胞和TIM-3⁺CD8⁺ T细胞的频率在慢性肝炎阶段最高。我们的研究结果表明，HBeAg状态与肝内CD8⁺ T细胞和NK细胞的独特免疫表型相关，其特征是ICM，特别是4-1BB的高表达。重要的是，抗病毒治疗部分恢复了ICM的正常表达。最后，我们描述了HBV患者肝内和循环NK细胞之间ICM表达的重要差异。

结论

我们的研究表明，慢性HBV患者肝内NK细胞和T细胞上ICM的表达根据其临床阶段存在明显差异。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/6c0938d18f58/fimmu-15-1489770-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/13721cb0eb77/fimmu-15-1489770-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/959c8da6fb13/fimmu-15-1489770-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/7cf921fd9500/fimmu-15-1489770-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/7a256df61c35/fimmu-15-1489770-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/6c0938d18f58/fimmu-15-1489770-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/13721cb0eb77/fimmu-15-1489770-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/959c8da6fb13/fimmu-15-1489770-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/7cf921fd9500/fimmu-15-1489770-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/7a256df61c35/fimmu-15-1489770-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8952/11774737/6c0938d18f58/fimmu-15-1489770-g005.jpg

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