新生儿体内的 PD-1 信号抑制 CD8+ T 细胞功能并保护其免受呼吸道病毒免疫病理的影响。

IF 7.9 2区 医学 Q1 IMMUNOLOGY Mucosal Immunology Pub Date : 2024-06-01 DOI:10.1016/j.mucimm.2023.12.004
Taylor Eddens , Olivia B. Parks , Yu Zhang , Michelle L. Manni , Jean-Laurent Casanova , Masato Ogishi , John V. Williams
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引用次数: 0

摘要

包括人类偏肺病毒(HMPV)在内的呼吸道病毒感染仍然是新生儿和婴儿发病和死亡的主要原因。然而,人们对新生儿对这些呼吸道病毒感染的敏感性增加背后的机制却知之甚少。与成人不同,新生儿的肺部具有多种抗炎机制,包括抑制受体 PD-1 的配体 PD-L1 的基线表达升高。因此,我们假设新生儿会依赖 PD-1:PD-L1 信号来抑制抗病毒 CD8 反应。为了验证这一假设,我们使用 WT C57BL/6 (B6) 和 Pdcd1-/-(缺乏 PD-1)小鼠建立了新生儿原发性 HMPV 感染模型。与成年 B6 小鼠相比,HMPV 感染的新生小鼠先天性免疫细胞上的 PD-L1/PD-L2 共表达增加,但抗原特异性 CD8+ T 细胞的数量和 PD-1 的上调情况相似。与成年 B6 小鼠相比,新生儿 CD8+ T 细胞产生的 IFN-γ、粒酶 B 和 IL-2 减少了。与 B6 新生儿相比,Pdcd1-/-新生 CD8+ T 细胞产生的 IFN-γ 和颗粒酶 B 明显增加。Pdcd1-/-新生儿在感染HMPV或流感后急性病理变化增加。感染了HMPV的Pdcd1-/-新生儿的肺部生理机能会发生长期变化,并伴有免疫病理和CD8+T细胞持续反应的证据,同时颗粒酶B的生成也会增加。通过对缺乏 PD-1 信号的患儿进行单细胞 RNA 测序,观察到了类似的活化 CD8+ T 细胞特征,颗粒酶 B 表达增加。这些数据表明,PD-1 信号传导严重限制了 CD8+ T 细胞效应功能,并防止了新生儿呼吸道病毒感染引起的免疫病理反应。
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PD-1 signaling in neonates restrains CD8+ T cell function and protects against respiratory viral immunopathology

Respiratory viral infections, including human metapneumovirus (HMPV), remain a leading cause of morbidity and mortality in neonates and infants. However, the mechanisms behind the increased sensitivity to those respiratory viral infections in neonates are poorly understood. Neonates, unlike adults, have several anti-inflammatory mechanisms in the lung, including elevated baseline expression of programmed death ligand 1 (PD-L1), a ligand for the inhibitory receptor programmed cell death protein 1 (PD-1). We thus hypothesized that neonates would rely on PD-1:PD-L1 signaling to restrain antiviral CD8 responses. To test this, we developed a neonatal primary HMPV infection model using wild-type C57BL/6 (B6) and Pdcd1-/- (lacking PD-1) mice. HMPV-infected neonatal mice had increased PD-L1/PD-L2 co-expression on innate immune cells but a similar number of antigen-specific CD8+ T cells and upregulation of PD-1 to that of adult B6 mice. Neonatal CD8+ T cells had reduced interferon‐gamma (IFN-γ), granzyme B, and interleukin-2 production compared with B6 adults. Pdcd1-/- neonatal CD8+ T cells had markedly increased production of IFN-γ and granzyme B compared with B6 neonates. Pdcd1-/- neonates had increased acute pathology with HMPV or influenza. Pdcd1-/- neonates infected with HMPV had long-term changes in pulmonary physiology with evidence of immunopathology and a persistent CD8+ T-cell response with increased granzyme B production. Using single-cell ribonucleic acid sequencing from a child lacking PD-1 signaling, a similar activated CD8+ T-cell signature with increased granzyme B expression was observed. These data indicate that PD-1 signaling critically limits CD8+ T-cell effector functions and prevents immunopathology in response to neonatal respiratory viral infections.

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来源期刊
Mucosal Immunology
Mucosal Immunology 医学-免疫学
CiteScore
16.60
自引率
3.80%
发文量
100
审稿时长
12 days
期刊介绍: Mucosal Immunology, the official publication of the Society of Mucosal Immunology (SMI), serves as a forum for both basic and clinical scientists to discuss immunity and inflammation involving mucosal tissues. It covers gastrointestinal, pulmonary, nasopharyngeal, oral, ocular, and genitourinary immunology through original research articles, scholarly reviews, commentaries, editorials, and letters. The journal gives equal consideration to basic, translational, and clinical studies and also serves as a primary communication channel for the SMI governing board and its members, featuring society news, meeting announcements, policy discussions, and job/training opportunities advertisements.
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