Human lung CD1c dendritic cells orchestrate lymphoid neogenesis during COPD

Introduction: Emerging evidence supports a crucial role for tertiary lymphoid organs (TLO) in chronic obstructive pulmonary disease (COPD) progression. However, mechanisms underlying TLO generation during COPD remain to be defined. Aim: We hypothesize that induction of T follicular helper (Tfh)-cells, specialized CD4+ T-cells key for TLO formation, by lung dendritic cells (DC) represents a crucial step in TLO neogenesis during COPD. Methods: We isolated different antigen-presenting cells (APC) from human COPD lung resections and assessed their potential to induce Tfh-cells. Results: Single cell RNA sequencing of lung HLA-DR+ cells revealed the presence of 6 APC populations. Compared to other APC subsets, CD1c+ DC showed a 2-fold increase in IL-21+ Tfh-cell induction. Importantly, the capacity of COPD CD1c+ DC to induce Tfh-cells, including IL-21 production, was even further increased 2-fold as compared to control CD1c+ DC. Moreover, increased Tfh-induction by COPD CD1c+ DC correlated with increased presence of Tfh-like cells in COPD lungs as compared to controls (5% vs 12% of CD4+ T-cells). Mechanistically, we found that CD1c+ DC exhibited a unique migratory signature, including expression of the oxysterol receptor EBI2. This enabled CD1c+ DC to efficiently migrate to and localize at the site of Tfh-cell and TLO generation during COPD. Secondly, compared to control DC, COPD CD1c+ DC expressed 3-fold increased OX40L levels. Importantly, blocking OX40L in the co-cultures reduced Tfh-cell formation with 40%. Conclusion: This study demonstrates that lung CD1c+ DC orchestrate TLO formation during COPD by inducing IL-21+ Tfh-cells, in which strategic localization and the OX40L-OX40 axis are critically implicated.