The long-term physiological consequences of respiratory viral infections, particularly in the aftermath of the COVID-19 pandemic—termed post-acute sequelae of SARS-CoV-2 (PASC)—are rapidly evolving into a major public health concern^1,2,3. While the cellular and molecular aetiologies of these sequelae are poorly defined, increasing evidence implicates abnormal immune responses^3,4,5,6 and/or impaired organ recovery^7,8,9 after infection. However, the precise mechanisms that link these processes in the context of PASC remain unclear. Here, with insights from three cohorts of patients with respiratory PASC, we established a mouse model of post-viral lung disease and identified an aberrant immune–epithelial progenitor niche unique to fibroproliferation in respiratory PASC. Using spatial transcriptomics and imaging, we found a central role for lung-resident CD8⁺ T cell–macrophage interactions in impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Specifically, IFNγ and TNF derived from CD8⁺ T cells stimulated local macrophages to chronically release IL-1β, resulting in the long-term maintenance of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFNγ + TNF or IL-1β markedly improved alveolar regeneration and pulmonary function. In contrast to other approaches, which require early intervention¹⁰, we highlight therapeutic strategies to rescue fibrotic disease after the resolution of acute disease, addressing a current unmet need in the clinical management of PASC and post-viral disease.

呼吸道病毒感染的长期生理后果，尤其是在 COVID-19 大流行之后——称为 SARS-CoV-2 急性后遗症 （PASC）——正在迅速演变为一个主要的公共卫生问题^1,2,3。虽然这些后遗症的细胞和分子病因尚不清楚，但越来越多的证据表明感染后免疫反应异常^3,4,5,6 和/或器官恢复受损^7,8,9。然而，在 PASC 背景下将这些过程联系起来的确切机制仍不清楚。在这里，凭借来自三组呼吸性 PASC 患者的见解，我们建立了病毒后肺病的小鼠模型，并确定了呼吸性 PASC 纤维化增殖特有的异常免疫上皮祖细胞生态位。使用空间转录组学和成像，我们发现肺驻留 CD8 ⁺ T 细胞-巨噬细胞相互作用在损害急性病毒性肺炎后肺泡再生和驱动纤维化后遗症中起着核心作用。具体来说，来源于 CD8⁺ T 细胞的 IFNγ 和 TNF 刺激局部巨噬细胞慢性释放 IL-1β，导致发育不良上皮祖细胞和肺纤维化的长期维持。值得注意的是，IFNγ + TNF 或 IL-1β 的治疗性中和显着改善了肺泡再生和肺功能。与其他需要早期干预的方法¹⁰ 相比，我们强调了在急性疾病消退后挽救纤维化疾病的治疗策略，解决了当前 PASC 和病毒后疾病临床管理中未满足的需求。