Lung IFNAR1(hi) TNFR2(+) cDC2 promotes lung regulatory T cells induction and maintains lung mucosal tolerance at steady state

The lung is a naturally tolerogenic organ. Lung regulatory T cells (T-regs) control lung mucosal tolerance. Here, we identified a lung IFNAR1(hi)TNFR2(+) conventional DC2 (iR2D2) population that induces T-regs in the lung at steady state. Using conditional knockout mice, adoptive cell transfer, receptor blocking antibodies, and TNFR2 agonist, we showed that iR2D2 is a lung microenvironment-adapted dendritic cell population whose residence depends on the constitutive TNFR2 signaling. IFNβ-IFNAR1 signaling in iR2D2 is necessary and sufficient for T-regs induction in the lung. The Epcam(+)CD45(−) epithelial cells are the sole lung IFNβ producer at the steady state. Surprisingly, iR2D2 is plastic. In a house dust mite model of asthma, iR2D2 generates lung T(H)2 responses. Last, healthy human lungs have a phenotypically similar tolerogenic iR2D2 population, which became pathogenic in lung disease patients. Our findings elucidate lung epithelial cells IFNβ-iR2D2-T-regs axis in controlling lung mucosal tolerance and provide new strategies for therapeutic interventions.