TLR7 Stimulation of APCs Results in Inhibition of IL-5 through Type I IFN and Notch Signaling Pathways in Human Peripheral Blood Mononuclear Cells

Abstract

TLR7 agonists modulate Th2 immune responses through mechanisms that have not been fully elucidated. Suppression of IL-5 production from Ag- or phytohemagglutinin-stimulated human PBMCs by the TLR7 antedrug AZ12441970 was mediated via type I IFN-dependent and type I IFN-independent mechanisms through TLR7 activation of plasmacytoid dendritic cells, B cells, and monocytes. The type I IFN-dependent inhibition of T cell-derived IL-5 was mediated by IFN-α acting directly on activated T cells. IL-10 was shown not to be involved in the type I IFN-independent inhibition of IL-5 and the mechanism of inhibition required cell-cell interaction. Notch signaling was implicated in the inhibition of IL-5, because addition of a γ-secretase inhibitor blocked the type I IFN-independent suppression of IL-5. Accordingly, AZ12441970 induced high levels of the notch ligands Dll1 and Dll4 mRNA, whereas immobilized DLL4 resulted in the suppression of IL-5 production. Therefore, we have elucidated two mechanisms whereby TLR7 agonists can modulate IL-5 production in human T cells. The suppression of Th2 cytokines, including IL-5, would be of benefit in diseases such as atopic asthma, so we assessed TLR7 function in PBMC from asthmatics and showed equivalent activity compared with healthy volunteers. Demonstrating this function is intact in asthmatics and knowing it links to suppression of Th2 cytokines support the case for developing such compounds for the treatment of allergic disease.