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慢性乙型肝炎患者外周自然杀伤细胞表现出 T 细胞耗竭的多种分子特征。

Peripheral natural killer cells in chronic hepatitis B patients display multiple molecular features of T cell exhaustion.

机构信息

CIRI, Centre International de Recherche en Infectiologie, Team Innate Immunity in Infectious and Autoimmune Diseases, Univ Lyon, Inserm, Université Claude Bernard Lyon 1, CNRS, Lyon, France.

Service d'Immunologie biologique, Hôpital Lyon Sud, Hospices Civils de Lyon, Lyon, France.

出版信息

Elife. 2021 Jan 28;10:e60095. doi: 10.7554/eLife.60095.

DOI:10.7554/eLife.60095
PMID:33507150
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7870135/
Abstract

Antiviral effectors such as natural killer (NK) cells have impaired functions in chronic hepatitis B (CHB) patients. The molecular mechanism responsible for this dysfunction remains poorly characterised. We show that decreased cytokine production capacity of peripheral NK cells from CHB patients was associated with reduced expression of NKp30 and CD16, and defective mTOR pathway activity. Transcriptome analysis of patients NK cells revealed an enrichment for transcripts expressed in exhausted T cells suggesting that NK cell dysfunction and T cell exhaustion employ common mechanisms. In particular, the transcription factor TOX and several of its targets were over-expressed in NK cells of CHB patients. This signature was predicted to be dependent on the calcium-associated transcription factor NFAT. Stimulation of the calcium-dependent pathway recapitulated features of NK cells from CHB patients. Thus, deregulated calcium signalling could be a central event in both T cell exhaustion and NK cell dysfunction occurring during chronic infections.

摘要

抗病毒效应器（如自然杀伤 (NK) 细胞）在慢性乙型肝炎 (CHB) 患者中的功能受损。导致这种功能障碍的分子机制仍未得到很好的描述。我们表明，CHB 患者外周 NK 细胞的细胞因子产生能力下降与 NKp30 和 CD16 表达减少以及 mTOR 通路活性缺陷有关。对患者 NK 细胞的转录组分析显示，表达耗尽 T 细胞的转录本富集，表明 NK 细胞功能障碍和 T 细胞耗竭采用共同的机制。特别是，转录因子 TOX 及其几个靶基因在 CHB 患者的 NK 细胞中过度表达。该特征被预测依赖于钙相关转录因子 NFAT。钙依赖性途径的刺激再现了 CHB 患者 NK 细胞的特征。因此，钙信号的失调可能是慢性感染期间发生的 T 细胞耗竭和 NK 细胞功能障碍的核心事件。

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