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 (Tregs) 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 eight weeks 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, cDC1 were less likely to be retained in the lungs and instead were enriched in mediastinal lymph nodes. Co-culture with DCs from cDC1-deficient BATF3-/- mice induced greater expression of intracellular IL-17 protein by naïve lung CD4+ T cells compared to 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 to air-exposed mice ( p < 0.05). Naïve CD4+ T cells co-cultured with lung DCs from CS-exposed mice produced more IL-17 ( p < 0.01) than co-culture 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 towards IL-17 production, and could play a role in the Th17/Treg imbalance seen in COPD.