Phosphoinositide 3-kinase d regulates dectin-2 signaling and the generation of Th2 and Th17 immunity

Min Jung Lee, Eri Yoshimoto, Shinobu Saijo, Yoichiro Iwakura, Xin Lin, Howard R. Katz, Yoshihide Kanaoka, Nora A. Barrett

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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-κB-dependent generation of cytokines, such as IL-23, IL-6, and TNF-a, 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 PI3Kd 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 PI3Kd in bone marrow-derived dendritic cells. PI3Kd activity depends on spleen tyrosine kinase (Syk) and regulates the activity of protein kinase Cd, indicating that PI3Kd is a proximal Syk-dependent signaling intermediate. Inhibition of PI3Kd 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 PI3Kd 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 PI3Kd inhibitor during the sensitization of wild-type mice prevents the generation of D. farinae-induced pulmonary inflammation. These results demonstrate that PI3Kd regulates Dectin-2 signaling and its dendritic cell function.

Original languageEnglish (US)
Pages (from-to)278-287
Number of pages10
JournalJournal of Immunology
Volume197
Issue number1
DOIs
StatePublished - Jul 1 2016

ASJC Scopus subject areas

  • Immunology

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    Lee, M. J., Yoshimoto, E., Saijo, S., Iwakura, Y., Lin, X., Katz, H. R., Kanaoka, Y., & Barrett, N. A. (2016). Phosphoinositide 3-kinase d regulates dectin-2 signaling and the generation of Th2 and Th17 immunity. Journal of Immunology, 197(1), 278-287. https://doi.org/10.4049/jimmunol.1502485