Predominant lung cDC2 phenotype in cigarette smoke-exposed mice favors polarization of IL-17-producing CD4⁺ T cells

Chronic obstructive pulmonary disease (COPD) is characterized by a deficiency within the lungs of regulatory T cells and an excess of Th17 cells, termed T17/Treg imbalance. Conventional dendritic cells type-1 (cDC1) and type-2 (cDC2) are known to drive Treg and Th17 polarization, respectively, but their roles in COPD are incompletely understood. Using a murine cigarette smoke (CS)-exposure model, we found that after 8 wk of CS exposure, the percentage of lung cDC1, but not cDC2, was significantly decreased (P < 0.05) relative to air-exposed controls. Following intranasal adoptive transfer into naïve recipients, cDC1s were less likely to be retained in the lungs and instead were enriched in mediastinal lymph nodes. Coculture with DCs from cDC1-deficient BATF3^-/- mice induced greater expression of intracellular IL-17 protein by naïve lung CD4⁺ T cells compared with DCs from BATF3^+/+ mice (P < 0.001), which instead more greatly induced intracellular IFN-gamma. LPS-stimulated lung DCs from CS-exposed wild-type mice produced significantly higher amounts of the Th17-polarizing cytokines IL-6 and IL-23. Congruently, whole lung homogenates of CS-exposed mice had increased IL-17 protein expression compared with air-exposed mice (P < 0.05). Naïve CD4⁺ T cells cocultured with lung DCs from CS-exposed mice produced more IL-17 (P < 0.01) than coculture with lung DC from air-exposed mice. Thus, loss of cDC1 and predominance of cDC2 in the lungs of CS-exposed mice drive naïve CD4⁺ T cells toward IL-17 production and could play a role in the Th17/Treg imbalance seen in COPD.NEW & NOTEWORTHY Dendritic cell subsets play unique roles in chronic obstructive pulmonary disease (COPD) pathogenesis. We demonstrated that conventional DC type 1 (cDC1) are decreased, leading to a predominant cDC2 population in the lungs of a clinically relevant murine model of cigarette smoke exposure. This drives naive CD4⁺ T cells toward IL-17 production and could play a role in the Th17/Treg imbalance seen in COPD.