Olivia B Parks, Taylor Eddens, Jorna Sojati, Jie Lan, Yu Zhang, Tim D Oury, Manda Ramsey, John J Erickson, Craig A Byersdorfer, John V Williams
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Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8<sup>+</sup> T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8<sup>+</sup> T cells into Rag1<sup>-/-</sup> recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8<sup>+</sup> T cells exhibit a terminally exhausted TCF1/7<sup>-</sup> TOX<sup>+</sup> EOMES<sup>+</sup> phenotype. 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引用次数: 0
摘要
背景:下呼吸道感染是老年人严重发病和死亡的主要原因。尽管老年人一生中无处不在地暴露于常见的呼吸道病原体,而且几乎所有人都有血清阳性反应,但抗体却不能有效地保护老年人。因此,我们假设老年人的严重呼吸道疾病是由于 CD8+ T 细胞反应不足所致:结果:我们在这里建立了人类偏肺病毒感染(HMPV)的老年小鼠模型,与年轻成年小鼠相比,老年 C57BL/6 小鼠表现出更严重的体重减轻、临床疾病、肺部病理变化和病毒清除延迟。老龄小鼠产生的肺浸润 HMPV 表位特异性 CD8+ T 细胞较少。扩增的T细胞表现出更高的PD-1和其他抑制性受体表达,并且功能受损。将衰老的 T 细胞移植到年轻小鼠体内,反之亦然,以及将年轻与衰老的 CD8+ T 细胞收养性转移到 Rag1-/- 受体中,都能重现 HMPV 的衰老表型,这表明存在细胞内在的年龄相关缺陷。HMPV 特异性老化 CD8+ T 细胞表现出 TCF1/7- TOX+ EOMES+ 表型的终末衰竭。我们证实,在流感病毒感染期间,老龄 CD8+ T 细胞也会出现类似的终末衰竭:本研究发现,CD8+ T 细胞终末衰竭是老年人呼吸道病毒感染导致严重疾病的机制之一。
Terminally exhausted CD8+ T cells contribute to age-dependent severity of respiratory virus infection.
Background: Lower respiratory infections are a leading cause of severe morbidity and mortality among older adults. Despite ubiquitous exposure to common respiratory pathogens throughout life and near universal seropositivity, antibodies fail to effectively protect the elderly. Therefore, we hypothesized that severe respiratory illness in the elderly is due to deficient CD8+ T cell responses.
Results: Here, we establish an aged mouse model of human metapneumovirus infection (HMPV) wherein aged C57BL/6 mice exhibit worsened weight loss, clinical disease, lung pathology and delayed viral clearance compared to young adult mice. Aged mice generate fewer lung-infiltrating HMPV epitope-specific CD8+ T cells. Those that do expand demonstrate higher expression of PD-1 and other inhibitory receptors and are functionally impaired. Transplant of aged T cells into young mice and vice versa, as well as adoptive transfer of young versus aged CD8+ T cells into Rag1-/- recipients, recapitulates the HMPV aged phenotype, suggesting a cell-intrinsic age-associated defect. HMPV-specific aged CD8+ T cells exhibit a terminally exhausted TCF1/7- TOX+ EOMES+ phenotype. We confirmed similar terminal exhaustion of aged CD8+ T cells during influenza viral infection.
Conclusions: This study identifies terminal CD8+ T cell exhaustion as a mechanism of severe disease from respiratory viral infections in the elderly.
期刊介绍:
Immunity & Ageing is a specialist open access journal that was first published in 2004. The journal focuses on the impact of ageing on immune systems, the influence of aged immune systems on organismal well-being and longevity, age-associated diseases with immune etiology, and potential immune interventions to increase health span. All articles published in Immunity & Ageing are indexed in the following databases: Biological Abstracts, BIOSIS, CAS, Citebase, DOAJ, Embase, Google Scholar, Journal Citation Reports/Science Edition, OAIster, PubMed, PubMed Central, Science Citation Index Expanded, SCImago, Scopus, SOCOLAR, and Zetoc.