Phosphoinositide 3-Kinase δ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity

The C-type lectin receptor Dectin-2 can trigger the leukotriene C-4 synthase dependent generation of cysteinyl leukotrienes and the caspase-associated recruitment domain 9- and NF-kappa B dependent generation of cytokines, such as IL-23, IL-6, and TNF-alpha, to promote Th2 and Th17 immunity, respectively. Dectin-2 activation also elicits the type 2 cytokine IL-33, but the mechanism by which Dectin-2 induces these diverse innate mediators is poorly understood. In this study, we identify a common upstream requirement for PI3K delta activity for the generation of each Dectin-2 dependent mediator elicited by the house dust mite species, Dermatophagoides farinae, using both pharmacologic inhibition and small interfering RNA knockdown of PI3K delta in bone marrow derived dendritic cells. PI3K gamma activity depends on spleen tyrosine kinase (Syk) and regulates the activity of protein kinase C delta, indicating that PI3K delta is a proximal Syk-dependent signaling intermediate. Inhibition of PI3K delta also reduces cysteinyl leukotrienes and cytokines elicited by Dectin-2 cross-linking, confirming the importance of this molecule in Dectin-2 signaling. Using an adoptive transfer model, we demonstrate that inhibition of PI3K delta profoundly reduces the capacity of bone marrow derived dendritic cells to sensitize recipient mice for Th2 and Th17 pulmonary inflammation in response to D. farinae. Furthermore, administration of a PI3K delta inhibitor during the sensitization of wild-type mice prevents the generation of D. farinae-induced pulmonary inflammation. These results demonstrate that PI3K delta regulates Dectin-2 signaling and its dendritic cell function.