Human Lung Conventional Dendritic Cells Orchestrate Lymphoid Neogenesis during Chronic Obstructive Pulmonary Disease

Abstract

<b>Rationale:</b> 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.<b>Objectives:</b> 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.<b>Methods:</b> 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 <i>in vitro</i> capability of control and COPD lung DC subsets, sorted using a fluorescence-activated cell sorter, to polarize IL-21⁺CXCL13⁺ (IL-21-positive and C-X-C chemokine ligand type 13-positive) Tfh-like cells. <i>In situ</i> imaging analysis was performed on Global Initiative for Chronic Obstructive Lung Disease stage IV COPD lungs with TLOs.<b>Measurements and Main Results:</b> 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-21⁺CXCL13⁺ 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.<b>Conclusions:</b> 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.