| First Author | Lee MJ | Year | 2016 |
| Journal | J Immunol | Volume | 197 |
| Issue | 1 | Pages | 278-87 |
| PubMed ID | 27194783 | Mgi Jnum | J:388660 |
| Mgi Id | MGI:6756591 | Doi | 10.4049/jimmunol.1502485 |
| Citation | Lee MJ, et al. (2016) Phosphoinositide 3-Kinase delta Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity. J Immunol 197(1):278-87 |
| abstractText | The C-type lectin receptor Dectin-2 can trigger the leukotriene C4 synthase-dependent generation of cysteinyl leukotrienes and the caspase-associated recruitment domain 9- and NF-kappaB-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 PI3Kdelta 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 PI3Kdelta in bone marrow-derived dendritic cells. PI3Kdelta activity depends on spleen tyrosine kinase (Syk) and regulates the activity of protein kinase Cdelta, indicating that PI3Kdelta is a proximal Syk-dependent signaling intermediate. Inhibition of PI3Kdelta 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 PI3Kdelta 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 PI3Kdelta inhibitor during the sensitization of wild-type mice prevents the generation of D. farinae-induced pulmonary inflammation. These results demonstrate that PI3Kdelta regulates Dectin-2 signaling and its dendritic cell function. |
