Toll-like receptor-7-mediated activation of pDCs suppresses the ILC2-mediated airway hyperreactivity and inflammation through type-I interferon

Abstract

Abstract Type 2 innate lymphoid cells (ILC2s) are newly identified subset of immune cells that play important roles in the pathogenesis of allergic diseases and asthma. The regulatory mechanisms that control the function and homeostasis of ILC2s are incompletely understood. Plasmacytoid dendritic cells (pDCs) have been previously associated with maintaining respiratory tolerance. To identify a novel mechanism for alleviating ILC2-mediated asthma we investigated impact of pDCs on ILC2s and ILC2-mediated airway hyperreactivity and inflammation. We investigated human and murine ILC2s and used clinically relevant allergen, Alternaria Alternata, as well as IL-33, to activate ILC2s in several mouse models including BDCA-2-DTR transgenic and Interferon alpha receptor-1 deficient mice. We found that activation of pDCS by a Toll-like receptor-7 agonist, R848, suppresses ILC2-mediated AHR and airway inflammation and that depletion of pDCs reverses this suppression. Moreover, we found that pDCs suppress cytokine production and proliferation of ILC2s through the production of interferon alpha. Transcriptome analysis of both human and murine ILC2s confirms the activation of regulatory pathways in ILC2s by interferon alpha. In addition, activation of pDCs alleviates airway hyperreactivity and inflammation by suppressing ILC2’s function and survival. Our findings reveal a novel regulatory pathway in ILC2-mediated pulmonary inflammation with important clinical implications.