Acute lung allograft dysfunction (ALAD) is an imprecise syndrome denoting concern for the onset of chronic lung allograft dysfunction (CLAD). Mechanistic biomarkers are needed that stratify risk of ALAD progression to CLAD. We hypothesized that single cell investigation of bronchoalveolar lavage (BAL) cells at the time of ALAD would identify immune cells linked to progressive graft dysfunction. We prospectively collected BAL from consenting lung transplant recipients for single cell RNA sequencing. ALAD was defined by a ≥10% decrease in FEV not caused by infection or acute rejection and samples were matched to BAL from recipients with stable lung function. We examined cell compositional and transcriptional differences across control, ALAD with decline, and ALAD with recovery groups. We also assessed cell-cell communication. BAL was assessed for 17 ALAD cases with subsequent decline (ALAD declined), 13 ALAD cases that resolved (ALAD recovered), and 15 cases with stable lung function. We observed broad differences in frequencies of the 26 unique cell populations across groups (p = 0.02). A CD8 T cell (p = 0.04) and a macrophage cluster (p = 0.01) best identified ALAD declined from the ALAD recovered and stable groups. This macrophage cluster was distinguished by an anti-inflammatory signature and the CD8 T cell cluster resembled a Tissue Resident Memory subset. Anti-inflammatory macrophages signaled to activated CD8 T cells via class I HLA, fibronectin, and galectin pathways (p < 0.05). Recipients with discordance between these cells had a nearly 5-fold increased risk of severe graft dysfunction or death (HR 4.6, 95% CI 1.1–19.2, adjusted p = 0.03). We validated these key findings in 2 public genomic datasets. BAL anti-inflammatory macrophages may protect against CLAD by suppressing CD8 T cells. These populations merit functional and longitudinal assessment in additional cohorts.

中文翻译：

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巨噬细胞和 CD8 T 细胞不一致与急性肺同种异体移植功能障碍进展相关

急性同种异体肺移植功能障碍 (ALAD) 是一种不精确的综合征，表明对慢性同种异体肺移植功能障碍 (CLAD) 的发病存在担忧。需要机械生物标志物来对 ALAD 进展为 CLAD 的风险进行分层。我们假设在 ALAD 时对支气管肺泡灌洗 (BAL) 细胞进行单细胞研究将识别与进行性移植物功能障碍相关的免疫细胞。我们前瞻性地从同意的肺移植受者那里收集了 BAL 进行单细胞 RNA 测序。ALAD 的定义是非感染或急性排斥反应引起的 FEV 下降 ≥10%，并且样本与来自肺功能稳定的受者的 BAL 相匹配。我们检查了对照组、ALAD 衰退组和 ALAD 恢复组之间的细胞组成和转录差异。我们还评估了细胞间的通讯。对 BAL 进行了评估，其中 17 例 ALAD 随后下降（ALAD 下降），13 例 ALAD 缓解（ALAD 恢复），15 例肺功能稳定。我们观察到各组 26 种独特细胞群的频率存在广泛差异 (p = 0.02)。CD8 T 细胞 (p = 0.04) 和巨噬细胞簇 (p = 0.01) 最能识别 ALAD 从 ALAD 恢复组和稳定组中下降。该巨噬细胞簇具有抗炎特征，CD8 T 细胞簇类似于组织驻留记忆子集。抗炎巨噬细胞通过 I 类 HLA、纤连蛋白和半乳糖凝集素途径向激活的 CD8 T 细胞发出信号 (p < 0.05)。这些细胞之间不一致的受体，严重移植物功能障碍或死亡的风险增加近 5 倍（HR 4.6，95% CI 1.1-19.2，调整后 p = 0.03）。我们在两个公共基因组数据集中验证了这些关键发现。BAL 抗炎巨噬细胞可能通过抑制 CD8 T 细胞来预防 CLAD。这些人群值得在其他队列中进行功能和纵向评估。