PD-1在急性病毒性呼吸道感染中损害老年小鼠CD8+ T细胞颗粒酶B的产生

Q3 Medicine
Olivia B Parks, Danielle Antos, Taylor Eddens, Sara Walters, Monika Johnson, Tim D Oury, Rachel A Gottschalk, John J Erickson, John V Williams
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引用次数: 0

摘要

CD8+ T细胞功能障碍有助于老年人严重呼吸道病毒感染的结果。CD8+ T细胞是负责病毒清除的主要细胞类型。随着年龄的增长,CD8+ T细胞功能下降,并伴有细胞毒性组织驻留记忆(TRM) CD8+ T细胞的积累。鉴于PD-1在急性和慢性感染期间调节CD8+ T细胞的重要性,我们试图阐明PD-1信号在急性病毒性呼吸道感染期间衰老的CD8+ T细胞功能和CD8+ TRM细胞积累中的作用。老年小鼠PD-1阻断或基因消融可提高CD8+ T细胞颗粒酶B的产生,与幼年小鼠在人偏肺病毒和流感病毒感染期间的表现相当。同基因移植和过继转移策略表明,衰老的Pdcd1-/- CD8+ T细胞中颗粒酶B产量的提高主要是细胞内在的,因为衰老的野生型CD8+ T细胞在移植到年轻宿主时没有增加颗粒酶B的产量。PD-1信号传导促进衰老小鼠细胞毒性CD8+ TRM细胞的积累。在再挑战感染期间,PD-1阻断老年小鼠可改善临床结果,同时减少CD8+ TRM细胞的积累。这些发现表明,PD-1信号通路损害了CD8+ T细胞颗粒酶B的产生,并促进了CD8+ TRM细胞在老年肺中的积累。这些发现对未来研究PD-1检查点抑制剂作为严重呼吸道病毒感染老年患者的潜在治疗选择具有重要意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PD-1 Impairs CD8+ T Cell Granzyme B Production in Aged Mice during Acute Viral Respiratory Infection.

CD8+ T cell dysfunction contributes to severe respiratory viral infection outcomes in older adults. CD8+ T cells are the primary cell type responsible for viral clearance. With increasing age, CD8+ T cell function declines in conjunction with an accumulation of cytotoxic tissue-resident memory (TRM) CD8+ T cells. We sought to elucidate the role of PD-1 signaling on aged CD8+ T cell function and accumulation of CD8+ TRM cells during acute viral respiratory tract infection, given the importance of PD-1 regulating CD8+ T cells during acute and chronic infections. PD-1 blockade or genetic ablation in aged mice yielded improved CD8+ T cell granzyme B production comparable to that in young mice during human metapneumovirus and influenza viral infections. Syngeneic transplant and adoptive transfer strategies revealed that improved granzyme B production in aged Pdcd1-/- CD8+ T cells was primarily cell intrinsic because aged wild-type CD8+ T cells did not have increased granzyme B production when transplanted into a young host. PD-1 signaling promoted accumulation of cytotoxic CD8+ TRM cells in aged mice. PD-1 blockade of aged mice during rechallenge infection resulted in improved clinical outcomes that paralleled reduced accumulation of CD8+ TRM cells. These findings suggest that PD-1 signaling impaired CD8+ T cell granzyme B production and contributed to CD8+ TRM cell accumulation in the aged lung. These findings have implications for future research investigating PD-1 checkpoint inhibitors as a potential therapeutic option for elderly patients with severe respiratory viral infections.

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CiteScore
3.70
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