Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58202, USA.
Sci Adv. 2024 Jan 5;10(1):eadj1120. doi: 10.1126/sciadv.adj1120. Epub 2024 Jan 3.
The dual role of CD8 T cells in influenza control and lung pathology is increasingly appreciated. To explore whether protective and pathological functions can be linked to specific subsets, we dissected CD8 T responses in influenza-infected murine lungs. Our single-cell RNA-sequencing (scRNA-seq) analysis revealed notable diversity in CD8 T subpopulations during peak viral load and infection-resolved state. While enrichment of a Cxcr3 CD8 T effector subset was associated with a more robust cytotoxic response, both CD8 T effector and central memory exhibited equally potent effector potential. The scRNA-seq analysis identified unique regulons regulating the cytotoxic response in CD8 T cells. The late-stage CD8 T blockade in influenza-cleared lungs or continuous CXCR3 blockade mitigated lung injury without affecting viral clearance. Furthermore, adoptive transfer of wild-type CD8 T cells exacerbated influenza lung pathology in Cxcr3 mice. Collectively, our data imply that CXCR3 interception could have a therapeutic effect in preventing influenza-linked lung injury.
CD8 T 细胞在流感控制和肺部病理中的双重作用正日益受到重视。为了探究保护性和病理性功能是否与特定亚群相关，我们剖析了流感感染的小鼠肺部中的 CD8 T 反应。我们的单细胞 RNA 测序（scRNA-seq）分析显示，在病毒载量峰值和感染缓解状态下，CD8 T 亚群表现出显著的多样性。虽然 Cxcr3 CD8 T 效应子亚群的富集与更强大的细胞毒性反应相关，但 CD8 T 效应子和中央记忆细胞均表现出同等强大的效应功能。scRNA-seq 分析确定了调节 CD8 T 细胞细胞毒性反应的独特调控因子。流感清除肺部晚期的 CD8 T 阻断或持续的 CXCR3 阻断减轻了肺损伤而不影响病毒清除。此外，野生型 CD8 T 细胞的过继转移加剧了 Cxcr3 小鼠的流感相关肺病理。总的来说，我们的数据表明，CXCR3 阻断可能具有预防流感相关肺损伤的治疗效果。
