Translational Science and Experimental Medicine, Research and Early Development, Respiratory, Inflammation, Autoimmunity.
Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), and.
Am J Respir Crit Care Med. 2020 Aug 15;202(4):535-548. doi: 10.1164/rccm.201906-1123OC.
Emerging evidence supports a crucial role for tertiary lymphoid organs (TLOs) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms of immune cell activation leading to TLOs in COPD remain to be defined. To examine the role of lung dendritic cells (DCs) in T follicular helper (Tfh)-cell induction, a T-cell subset critically implicated in lymphoid organ formation, in COPD. Myeloid cell heterogeneity and phenotype were studied in an unbiased manner via single-cell RNA sequencing on HLA-DR cells sorted from human lungs. We measured the capability of control and COPD lung DC subsets, sorted using a fluorescence-activated cell sorter, to polarize IL-21CXCL13 (IL-21-positive and C-X-C chemokine ligand type 13-positive) Tfh-like cells. imaging analysis was performed on Global Initiative for Chronic Obstructive Lung Disease stage IV COPD lungs with TLOs. Single-cell RNA-sequencing analysis revealed a high degree of heterogeneity among human lung myeloid cells. Among these, conventional dendritic type 2 cells (cDC2s) showed increased induction of IL-21CXCL13 Tfh-like cells. Importantly, the capacity to induce IL-21 Tfh-like cells was higher in cDC2s from patients with COPD than in those from control patients. Increased Tfh-cell induction by COPD cDC2s correlated with increased presence of Tfh-like cells in COPD lungs as compared with those in control lungs, and cDC2s colocalized with Tfh-like cells in TLOs of COPD lungs. Mechanistically, cDC2s exhibited a unique migratory signature and (transcriptional) expression of several pathways and genes related to DC-induced Tfh-cell priming. Importantly, blocking the costimulatory OX40L (OX40 ligand)-OX40 axis reduced Tfh-cell induction by control lung cDC2s. In COPD lungs, we found lung EBI2 (Epstein-Barr virus-induced gene 2-positive) OX-40L-expressing cDC2s that induced IL-21 Tfh-like cells, suggesting an involvement of these cells in TLO formation.
越来越多的证据表明，三级淋巴器官（TLOs）在慢性阻塞性肺疾病（COPD）的进展中起着关键作用。然而，导致 COPD 中 TLO 形成的免疫细胞激活机制仍有待确定。为了研究肺树突状细胞（DCs）在滤泡辅助性 T 细胞（Tfh）细胞诱导中的作用，这是一种在淋巴器官形成中起关键作用的 T 细胞亚群。我们通过对人类肺部分离的 HLA-DR 细胞进行单细胞 RNA 测序，以无偏倚的方式研究髓样细胞异质性和表型。我们测量了使用荧光激活细胞分选术分选的对照和 COPD 肺 DC 亚群极化 IL-21CXCL13（IL-21 阳性和 C-X-C 趋化因子配体 13 阳性）Tfh 样细胞的能力。对具有 TLO 的 IV 期 COPD 肺部进行了全球倡议慢性阻塞性肺疾病（GOLD）分期的成像分析。单细胞 RNA-seq 分析显示，人类肺髓样细胞具有高度的异质性。在这些细胞中，传统的树突状细胞 2 型（cDC2）显示出诱导 IL-21CXCL13 Tfh 样细胞的能力增加。重要的是，与对照患者相比，COPD 患者的 cDC2 诱导 IL-21 Tfh 样细胞的能力更高。COPD cDC2 诱导 Tfh 细胞的增加与 COPD 肺部中 Tfh 样细胞的存在增加相关，并且 cDC2 与 COPD 肺部 TLO 中的 Tfh 样细胞共定位。从机制上讲，cDC2 表现出独特的迁移特征和与 DC 诱导 Tfh 细胞启动相关的几种途径和基因的（转录）表达。重要的是，阻断共刺激 OX40L（OX40 配体）-OX40 轴可减少对照肺 cDC2 诱导的 Tfh 细胞的诱导。在 COPD 肺部中，我们发现肺 EBI2（Epstein-Barr 病毒诱导基因 2 阳性）OX-40L 表达的 cDC2 诱导 IL-21 Tfh 样细胞，表明这些细胞参与了 TLO 的形成。
