Ifnβ Reprograms Th2 Promoting Mature Lung TNFR2+ cDC2 Subset <i>in vivo</i> to Generate Regulatory T Cells and Restore Lung Mucosal Tolerance

Abstract

Lung dendritic cells and regulatory T cells control lung mucosal tolerance. Here, we identified a lung-resident IDO-1+TNFR2+ conventional DC2 (iR2D2) subset that induces antigen-specific regulatory T cells in the lung. iR2D2 is a microenvironment specialized DC subset whose existence depends on its constitutive TNFR2-pRelB-IDO-1 signaling. The iR2D2 intrinsic IFNAR-TGFβ1 signaling is necessary and sufficient for regulatory T cells induction in vivo. Surprisingly, iR2D2 is plastic. In a house dust mite (HDM) model of asthma, iR2D2 generates lung Th2 responses. Remarkably, intranasally administration of IFNβ reprogramed HDM-induced Th2-promoting iR2D2 back to generate regulatory T cells, reversed lung inflammation and protected mice from subsequent asthma exacerbation. Healthy human lung has a phenotypically similar tolerogenic iR2D2, which became IL-4+ in emphysema patients. Finally, IFNβ successfully reprogramed human emphysema iR2D2 ex vivo. These findings elucidate a fundamental mechanism controlling lung tolerance and a strategy to restore lung tolerance in inflammatory lung diseases.